{"gene":"SIRT7","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2006,"finding":"SIRT7 localizes to the nucleolus, associates with active rRNA genes (rDNA), interacts with RNA Polymerase I and histones, and positively regulates Pol I-mediated transcription; knockdown reduces Pol I association with rDNA and decreases rRNA transcription, while overexpression increases it.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, overexpression with transcription assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, ChIP, and functional transcription assays in the same study; independently referenced by many subsequent papers","pmids":["16618798"],"is_preprint":false},{"year":2008,"finding":"SIRT7 interacts with p53 and deacetylates p53 in vitro; Sirt7 knockout mice show hyperacetylation of p53 in vivo and increased cardiomyocyte apoptosis, indicating SIRT7 suppresses p53-dependent apoptosis in the heart.","method":"Co-immunoprecipitation, in vitro deacetylation assay, Sirt7 knockout mouse model, immunoblot for acetylated p53","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro deacetylation confirmed plus in vivo knockout with acetylation phenotype; independently replicated in later studies","pmids":["18239138"],"is_preprint":false},{"year":2012,"finding":"SIRT7 is an NAD+-dependent H3K18Ac deacetylase that binds promoters of tumor-suppressive genes through interaction with the ETS transcription factor ELK4, deacetylates H3K18Ac to repress transcription, and is necessary for maintaining cancer cell transformation and global H3K18Ac hypoacetylation.","method":"Genome-wide ChIP-seq, in vitro deacetylation assay, siRNA knockdown, xenograft mouse model, co-immunoprecipitation with ELK4","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deacetylase assay plus genome-wide binding, functional knockout, and in vivo xenograft; multiple orthogonal methods in a single rigorous study","pmids":["22722849"],"is_preprint":false},{"year":2013,"finding":"SIRT7 nuclear/nucleolar localization is governed by two distinct N-terminal (aa 61-76) and C-terminal (aa 392-400) sequence elements; a cytoplasmic pool of SIRT7 also exists, and loss of nucleolar SIRT7 associates with replicative senescence.","method":"Deletion constructs, site-directed mutagenesis, immunocytochemistry, subcellular fractionation, RNAi, peptide competition assay","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis combined with fractionation and imaging in multiple cell types; single lab but multiple orthogonal methods","pmids":["23680022"],"is_preprint":false},{"year":2013,"finding":"SIRT7 functions at chromatin as an NAD+-dependent H3K18Ac deacetylase that interacts with the transcription factor Myc at ribosomal protein gene promoters to silence expression and relieve ER stress; SIRT7-deficient mice develop chronic hepatosteatosis.","method":"ChIP, co-immunoprecipitation with Myc, siRNA knockdown, Sirt7 knockout mouse model, pharmacologic ER stress suppression rescue","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, co-IP, KO mouse model with rescue experiments; multiple orthogonal methods","pmids":["24210820"],"is_preprint":false},{"year":2014,"finding":"SIRT7 deacetylates GABPβ1 at specific lysine residues in its dimerization domains, facilitating GABPβ1/GABPα complex formation and transcriptional activation of nuclear-encoded mitochondrial genes; Sirt7 deficiency in mice causes multisystemic mitochondrial dysfunction.","method":"In vitro deacetylation assay, co-immunoprecipitation, Sirt7 knockout mouse model with mitochondrial functional measurements, rescue with SIRT7 overexpression in patient fibroblasts","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deacetylation assay, co-IP, KO mouse phenotype, and human disease cell rescue; multiple orthogonal methods","pmids":["25200183"],"is_preprint":false},{"year":2014,"finding":"SIRT7 binds the DCAF1/DDB1/CUL4B E3 ubiquitin ligase complex and inhibits it from ubiquitinating and degrading the nuclear receptor TR4, thereby upregulating TR4 target genes that promote fatty acid uptake and triglyceride synthesis in liver.","method":"Co-immunoprecipitation, ubiquitination assay, Sirt7 knockout mouse on high-fat diet, liver-specific Sirt7 knockout","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of multi-protein complex, in vivo KO phenotype confirmed in liver-specific KO; multiple orthogonal approaches","pmids":["24703702"],"is_preprint":false},{"year":2015,"finding":"SIRT7 directly interacts with SIRT1, representing the first demonstration of direct interaction and functional interplay between two mammalian sirtuins; SIRT7 inactivation suppresses metastasis in vivo in both epithelial and mesenchymal cancer models.","method":"Co-immunoprecipitation, in vivo metastasis assay, siRNA knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP for interaction, in vivo metastasis suppression; single lab, limited mechanistic depth on the SIRT1 interaction","pmids":["25923013"],"is_preprint":false},{"year":2016,"finding":"SIRT7 is recruited to DNA double-strand break (DSB) sites in a PARP1-dependent manner, where it deacetylates H3K18Ac to promote 53BP1 recruitment and efficient non-homologous end joining (NHEJ) repair; SIRT7-deficient mice show increased replication stress and a progeroid phenotype.","method":"Chromatin immunoprecipitation at DSBs, PARP1 dependency experiments, NHEJ repair assay, SIRT7 knockout mouse model, 53BP1 focal accumulation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at DSB sites, mechanistic PARP1 dependency, NHEJ assay, and in vivo KO phenotype in one study","pmids":["27225932"],"is_preprint":false},{"year":2016,"finding":"SIRT7 deacetylates U3-55k, a core component of the U3 snoRNP complex; deacetylation enhances U3-55k binding to U3 snoRNA, which is required for pre-rRNA cleavage steps generating 18S rRNA. Under stress, SIRT7 is released from nucleoli, causing hyperacetylation of U3-55k and attenuation of pre-rRNA processing.","method":"In vitro deacetylation assay, RNA immunoprecipitation, siRNA knockdown, rRNA processing assays, nucleolar fractionation under stress","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deacetylation assay plus RNA-protein binding assay and functional processing readout; multiple orthogonal methods","pmids":["26867678"],"is_preprint":false},{"year":2016,"finding":"DNA activates SIRT7 deacetylase activity in vitro, allowing it to deacetylate H3K18 in the chromatin context; both N- and C-termini are important for this DNA-activated activity, and the mechanism differs from that of SIRT6.","method":"In vitro deacetylation assay with DNA, truncation and mutagenesis, chromatin deacetylation assay","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis; single lab but rigorous biochemical approach","pmids":["26907567"],"is_preprint":false},{"year":2016,"finding":"RNA (especially rRNA) activates SIRT7 catalytic efficiency even more potently than DNA, and SIRT7 can remove long-chain fatty acyl groups from lysines (defatty-acylase activity) more efficiently than acetyl groups; truncation/mutagenesis identified N- and C-terminal residues involved in RNA binding and activity. RIP-seq identified rRNA as the predominant RNA binding partner.","method":"In vitro deacetylase/defatty-acylase assay, RNA immunoprecipitation-sequencing, truncation/mutagenesis, metabolic labeling with alkyne-tagged fatty acid analog","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution plus mutagenesis plus metabolic labeling; multiple orthogonal methods in one study","pmids":["27997115"],"is_preprint":false},{"year":2017,"finding":"SIRT7 deacetylates DDX21 (a DEAD-box helicase); deacetylation by SIRT7 augments DDX21 helicase activity to unwind R-loops, while acetylation by CBP inhibits DDX21. Knockdown of SIRT7 phenocopies DDX21 depletion, causing R-loop accumulation and DNA double-strand breaks.","method":"In vitro helicase/deacetylation assay, siRNA knockdown, R-loop detection (S9.6 antibody), DNA damage assay, co-immunoprecipitation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deacetylation assay, in vitro helicase activity, genetic epistasis via dual knockdown, multiple orthogonal methods","pmids":["28790157"],"is_preprint":false},{"year":2017,"finding":"SIRT7 deacetylates SMAD4, promoting its degradation via β-TrCP1-mediated ubiquitination; SIRT7 deficiency stabilizes SMAD4, activates TGF-β signaling, and enhances epithelial-to-mesenchymal transition and breast cancer metastasis.","method":"Co-immunoprecipitation, in vitro deacetylation assay, ubiquitination assay, siRNA/shRNA knockdown, in vivo metastasis mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deacetylation, ubiquitination assay, co-IP, and in vivo metastasis suppression; multiple orthogonal methods","pmids":["28827661"],"is_preprint":false},{"year":2017,"finding":"SIRT7 deacetylates CDK9 (a subunit of P-TEFb) at lysine 48, counteracting GCN5-directed acetylation; deacetylation promotes P-TEFb release from the inactive 7SK snRNP complex and activates CDK9-mediated CTD phosphorylation and Pol II transcription elongation.","method":"Proteomic co-IP, in vitro deacetylation assay, ChIP, Pol II CTD phosphorylation assay, siRNA knockdown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deacetylation assay, identification of acetylation site (K48), P-TEFb release assay, and ChIP; multiple orthogonal methods","pmids":["28426094"],"is_preprint":false},{"year":2017,"finding":"SIRT7 deacetylates FKBP51 at K28 and K155, which enhances the interaction of FKBP51 with Akt and PHLPP, leading to Akt dephosphorylation; mutation of both lysines to arginine abolishes SIRT7-mediated Akt dephosphorylation.","method":"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis (K28R/K155R), phospho-Akt immunoblot, siRNA knockdown","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical deacetylation assay with mutagenesis ablation of function; single lab with multiple orthogonal methods","pmids":["28147277"],"is_preprint":false},{"year":2017,"finding":"Sirt7 restricts Sirt1 activity by preventing Sirt1 autodeacetylation; increased Sirt1 activity in Sirt7-/- mice blocks PPARγ and adipocyte differentiation, and reducing Sirt1 activity restores adipogenesis in Sirt7-/- cells.","method":"In vitro deacetylation assay, Sirt7 knockout mouse model, Sirt1 activity assays, adipocyte differentiation rescue experiments, genetic epistasis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model, in vitro deacetylation assay, and rescue epistasis experiments; multiple orthogonal methods","pmids":["28923965"],"is_preprint":false},{"year":2017,"finding":"USP7 interacts with SIRT7 and removes K63-linked polyubiquitin chains from SIRT7; while deubiquitination does not affect SIRT7 stability, it represses SIRT7 enzymatic activity. SIRT7 targets the G6PC gluconeogenic gene promoter through ELK4.","method":"Co-immunoprecipitation, in vitro deubiquitination assay, ubiquitination linkage analysis, in vitro deacetylation assay, ChIP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical deubiquitination assay, ubiquitin linkage specificity, functional activity assay; single lab with multiple orthogonal methods","pmids":["28655758"],"is_preprint":false},{"year":2017,"finding":"Sirt7 stabilizes rDNA heterochromatin by recruiting DNA methyltransferase 1 (DNMT1) and Sirt1 to rDNA loci; Sirt7 loss leads to nucleolar fragmentation, rDNA hypomethylation, and histone hyperacetylation at rDNA.","method":"Co-immunoprecipitation, ChIP, bisulfite sequencing (rDNA methylation), Sirt7 knockout cells/mice","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and co-IP in KO context; single lab, multiple methods but limited biochemical reconstitution","pmids":["28842251"],"is_preprint":false},{"year":2017,"finding":"SIRT7 deacetylates DDB1, reducing DDB1 binding to CUL4 and suppressing CRL4 E3 ubiquitin ligase activity; upon nucleolar stress (actinomycin D or 5-FU), SIRT7 redistributes from nucleolus to nucleoplasm to promote DDB1 deacetylation, leading to accumulation of CRL4 substrates including LATS1 and p73.","method":"In vitro deacetylation assay, co-immunoprecipitation, siRNA knockdown, actinomycin D/5-FU nucleolar stress treatment, immunoblot for CRL4 substrates","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical deacetylation assay, co-IP, and functional substrate accumulation with stress-dependent relocalization; single lab, multiple orthogonal methods","pmids":["28886238"],"is_preprint":false},{"year":2018,"finding":"SIRT7 deacetylates fibrillarin (FBL); hyperacetylation of FBL impairs its interaction with histone H2A and chromatin, compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high rRNA synthesis during interphase; at mitotic onset, hyperacetylation of FBL accompanies loss of H2AQ104me and Pol I repression.","method":"In vitro deacetylation assay (CBP acetylates, SIRT7 deacetylates FBL), acetylation-deficient/mimicking FBL mutants, H2AQ104me immunoblot, co-immunoprecipitation, ChIP","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deacetylation assay, mutagenesis, H2A methylation assay, and ChIP; multiple orthogonal methods in one study","pmids":["30540930"],"is_preprint":false},{"year":2018,"finding":"PRMT6 directly methylates SIRT7 at arginine 388 (R388) in vitro and in vivo, inhibiting its H3K18 deacetylase activity without altering subcellular localization. AMPK disrupts PRMT6-SIRT7 association, causing R388 hypomethylation. High glucose enhances R388 methylation, coupling glucose availability to mitochondria biogenesis via SIRT7.","method":"In vitro methylation assay, co-immunoprecipitation, SIRT7 deacetylase activity assay with R388 mutant, AMPK activation experiments, immunoblot in mouse liver","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical methylation assay, site-specific mutagenesis, functional enzymatic assay, and in vivo validation; multiple orthogonal methods","pmids":["30420520"],"is_preprint":false},{"year":2018,"finding":"SIRT7 interacts with and deacetylates PPARγ2 at K382; acetylation-mimicking K382Q mutation impairs lipogenesis gene expression (Srebp1c, Acaca, Fasn, Scd1) and reduces PPARγ2 transcriptional activity in adipocytes.","method":"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis (K382Q and K382R), global gene expression analysis, transcriptional activity assay","journal":"Journal of diabetes investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical deacetylation assay with mutagenesis and functional gene expression readout; single lab, multiple methods","pmids":["33955199"],"is_preprint":false},{"year":2019,"finding":"SIRT7 interacts with and deacetylates ATM in vitro and in vivo; SIRT7-mediated ATM deacetylation is prerequisite for ATM dephosphorylation by phosphatase WIP1. SIRT7 is mobilized onto chromatin during late stages of DNA damage response to deactivate ATM; SIRT7 depletion or acetylation-mimic ATM mutation causes persistent ATM phosphorylation and impaired DNA repair.","method":"Co-immunoprecipitation, in vitro deacetylation assay, chromatin fractionation, phospho-ATM immunoblot, acetylation-mimicking ATM mutation, DNA repair assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deacetylation assay, mutagenesis, chromatin recruitment assay, and functional DNA repair readout; multiple orthogonal methods","pmids":["30944854"],"is_preprint":false},{"year":2019,"finding":"SIRT7 mediates H3K18 deacetylation-dependent epigenetic repression of LINE-1 (L1) retrotransposons genome-wide; SIRT7 interacts with Lamin A/C to promote L1 association with the nuclear lamina. SIRT7 depletion causes increased L1 expression and retrotransposition.","method":"ChIP-seq, siRNA knockdown, L1 retrotransposition assay, co-immunoprecipitation with Lamin A/C, SIRT7 KO mouse and human cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq, co-IP, functional retrotransposition assay in mouse and human cells; multiple orthogonal methods","pmids":["31226208"],"is_preprint":false},{"year":2019,"finding":"SIRT7 deacetylates CRY1 and promotes its FBXL3-mediated degradation, thereby regulating the hepatic circadian clock. Body temperature oscillations drive HSP70 expression, which promotes SIRT7 ubiquitination and degradation, establishing a BT-HSP70-SIRT7-CRY1 axis coupling the hepatic clock to the central pacemaker.","method":"Co-immunoprecipitation, in vitro deacetylation assay, Sirt7 knockout mouse model with circadian phase analysis, ubiquitination assay, CRY1 stability assay","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deacetylation, ubiquitination assay, co-IP, and KO mouse circadian phenotype; multiple orthogonal methods","pmids":["32694864"],"is_preprint":false},{"year":2019,"finding":"SIRT7 forms a complex with MEF2D that attenuates MEF2D acetylation and reduces MEF2D-driven PD-L1 expression in hepatocellular carcinoma; IFNG-induced p300 acetylates MEF2D and disrupts the MEF2D-SIRT7 interaction, enabling PD-L1 transcription.","method":"Co-immunoprecipitation, pulldown assay, ChIP, dual luciferase reporter, SIRT7 knockout in cell lines and orthotopic mouse model","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, ChIP, reporter assay, and in vivo KO model; multiple orthogonal methods","pmids":["31678303"],"is_preprint":false},{"year":2020,"finding":"SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins to maintain repressive heterochromatin at the nuclear periphery; SIRT7 deficiency leads to loss of heterochromatin, de-repression of LINE1, and activation of innate immune signaling via the cGAS-STING pathway in human mesenchymal stem cells.","method":"Co-immunoprecipitation with Lamin and HP1 proteins, ChIP, LINE1 expression assay, cGAS-STING pathway activation assay, SIRT7 KD/KO in hMSCs","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of multi-protein complex, ChIP, functional innate immune activation assay; multiple orthogonal methods","pmids":["32504224"],"is_preprint":false},{"year":2020,"finding":"SirT7 exhibits auto-mono-ADP-ribosyltransferase (mADPRT) activity at a previously undefined active site distinct from its deacetylase active site; ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions and regulating gene expression involved in second-messenger signaling and autophagy.","method":"Mass spectrometry identification of ADP-ribosylation, site-directed mutagenesis of mADPRT active site, chromatin distribution assay, SirT7 KO mouse with calorie restriction","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical identification of novel activity, mutagenesis, chromatin redistribution assay, and in vivo KO; multiple orthogonal methods","pmids":["32832656"],"is_preprint":false},{"year":2020,"finding":"SIRT7 directly interacts with and deacetylates PCAF at K720; PCAF deacetylation augments its binding to MDM2 (the p53 E3 ligase), leading to MDM2 degradation, p21 upregulation, and cell-cycle arrest under glucose deprivation conditions.","method":"Co-immunoprecipitation, in vitro deacetylation assay, MDM2 ubiquitination/degradation assay, p21/p53 immunoblot under glucose deprivation, SIRT7 depletion","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical deacetylation assay, co-IP, and functional MDM2 degradation assay; single lab, multiple methods","pmids":["32404984"],"is_preprint":false},{"year":2020,"finding":"SIRT7 deacetylates NPM (nucleophosmin); ATR-mediated phosphorylation of SIRT7 upon UV irradiation increases its catalytic activity. Deacetylated NPM relocates to the nucleoplasm and binds MDM2, preventing p53 ubiquitination and degradation, thus stabilizing p53 during genotoxic stress.","method":"In vitro deacetylation assay, ATR phosphorylation assay, NPM relocalization assay, co-immunoprecipitation with MDM2, p53 stability assay in vitro and in vivo (KO mouse UV response)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deacetylation, phosphorylation assay, co-IP, and in vivo KO mouse validation; multiple orthogonal methods","pmids":["33495326"],"is_preprint":false},{"year":2020,"finding":"Progerin (HGPS mutant Lamin A) interacts with and destabilizes SIRT7; ectopic SIRT7 expression alleviates progerin-induced inflammatory response in vascular endothelial cells.","method":"Co-immunoprecipitation of progerin-SIRT7, endothelial cell overexpression, inflammatory marker assay, Tie2-Cre Lmna progerin knock-in mouse model","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP interaction plus functional rescue; in vivo mouse model but mechanistic depth of destabilization not fully biochemically dissected","pmids":["32128409"],"is_preprint":false},{"year":2021,"finding":"SIRT7 decrotonylates PHF5A at K25; this PHF5A decrotonylation contributes to decreased CDK2 expression via retained intron-induced abnormal alternative splicing, thereby accelerating fibroblast senescence.","method":"Mass spectrometry identification of crotonylation sites, SIRT7 knockdown/overexpression, immunoblot for Kcr, co-IP, CDK2 splicing analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based substrate identification with functional splicing readout; single lab, limited in vitro biochemical reconstitution of decrotonylation","pmids":["34604215"],"is_preprint":false},{"year":2022,"finding":"SIRT7 deacetylates insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), enhancing its inhibitory action on Ucp1 mRNA translation, thereby suppressing UCP1 protein levels and brown adipose tissue thermogenesis; Sirt7 knockout mice have higher body temperature and energy expenditure.","method":"Sirt7 whole-body and BAT-specific knockout mice, UCP1 protein immunoblot, in vitro deacetylation assay, Ucp1 mRNA translation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — tissue-specific KO with clear phenotype, biochemical deacetylation assay, and mRNA translation assay; multiple orthogonal methods","pmids":["36509749"],"is_preprint":false},{"year":2022,"finding":"O-GlcNAcylation of SIRT7 at serine 136 (S136) by OGT stabilizes SIRT7 protein by blocking its interaction with the proteasome activator REGγ, preventing SIRT7 degradation; SIRT7 O-GlcNAcylation is required for its H3K18 deacetylase activity and oncogenic function in pancreatic cancer.","method":"Mass spectrometry (OGT interaction and S136 modification), co-immunoprecipitation, S136A mutant, H3K18ac immunoblot, in vivo xenograft","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — MS identification of modification site, site-specific mutant, co-IP for REGγ interaction, and functional deacetylase assay; multiple orthogonal methods","pmids":["35422493"],"is_preprint":false},{"year":2023,"finding":"SIRT7 deacetylates FAM134B (an ER-phagy receptor), counteracting CBP-mediated acetylation that promotes ER-phagy; SIRT7-mediated deacetylation tempers FAM134B activity to avoid excessive ER degradation, maintaining ER homeostasis.","method":"Co-immunoprecipitation, in vitro deacetylation assay, ER-phagy assay, CBP/SIRT7 gain- and loss-of-function","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical deacetylation assay with co-IP and functional ER-phagy readout; single lab, multiple orthogonal methods","pmids":["37043189"],"is_preprint":false},{"year":2024,"finding":"SIRT7 suppresses MST1 (a Hippo pathway kinase) by two mechanisms: (1) binding to the MST1 promoter and inducing H3K18 deacetylation to repress transcription, and (2) directly binding and deacetylating MST1 protein, which primes acetylation-dependent MST1 ubiquitination and degradation; this promotes YAP nuclear localization and activation in hepatocellular carcinoma.","method":"ChIP, luciferase reporter assay, co-immunoprecipitation, mass spectrometry (deacetylation), ubiquitination assay, xenograft mouse model","journal":"Cancer science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP for transcriptional regulation, co-IP and MS for direct deacetylation, ubiquitination assay, and in vivo xenograft; multiple orthogonal methods","pmids":["38288904"],"is_preprint":false},{"year":2024,"finding":"SIRT7 deacetylates KLF4 (Krüppel-like factor 4) at K228, inhibiting its ubiquitination-proteasome degradation; the SIRT7/KLF4 axis maintains pulmonary arterial endothelial cell homeostasis; endothelium-specific SIRT7 depletion exacerbates pulmonary hypertension.","method":"Co-immunoprecipitation, deacetylation assay, ubiquitination assay, endothelium-specific Sirt7 KO mouse in SuHx PH model, AAV-mediated SIRT7 overexpression rescue","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deacetylation and ubiquitination assay, tissue-specific KO, and AAV rescue; multiple orthogonal methods","pmids":["38198357"],"is_preprint":false},{"year":2024,"finding":"SIRT7 interacts with DDX3X and deacetylates it; SIRT7-mediated DDX3X deacetylation promotes DDX3X protein stability. SIRT7 inhibition leads to DDX3X depletion, disruption of NLRP3 inflammasome assembly, and suppression of ERK1/2 signaling, re-sensitizing cells to sorafenib.","method":"Mass spectrometry (DDX3X as SIRT7 target), co-immunoprecipitation, DDX3X deacetylation assay, NLRP3 inflammasome assay, in vivo xenograft with SIRT7 inhibitors","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification plus co-IP and functional pathway assay; single lab, limited biochemical reconstitution depth","pmids":["38277756"],"is_preprint":false},{"year":2024,"finding":"SIRT7 directly interacts with KIF23 and catalyzes its desuccinylation at K537, which enhances KIF23 protein stability and promotes anaplastic thyroid cancer cell proliferation and migration.","method":"Co-immunoprecipitation, succinylation immunoblot with K537 mutant, SIRT7 overexpression/knockdown, cell viability and migration assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP and site-specific mutagenesis with functional readout; single lab, limited biochemical reconstitution of desuccinylation","pmids":["38360598"],"is_preprint":false},{"year":2024,"finding":"SIRT7 directly interacts with the GLUT3 enhancer region and desuccinylates H3K122 at that locus, repressing GLUT3 expression; SIRT7 knockdown upregulates GLUT3 and sensitizes pancreatic cancer cells to gemcitabine.","method":"ChIP, co-IP, H3K122 succinylation immunoblot, ATAC-seq/RNA-seq cross-analysis, SIRT7 KD with gemcitabine sensitivity assay, xenograft mouse model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and succinylation immunoblot with functional drug sensitivity readout; single lab, limited in vitro biochemical reconstitution of histone desuccinylation","pmids":["39002692"],"is_preprint":false},{"year":2017,"finding":"HDAC8 forms a complex with SMAD3/4 and occupies the SIRT7 promoter, where it deacetylates H4 to transcriptionally suppress SIRT7 expression; this establishes a TGF-β/HDAC8/SMAD3-4/SIRT7 regulatory feedback loop.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown of HDAC8/SMAD3/4, luciferase reporter assay, H4 acetylation immunoblot at SIRT7 promoter","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, co-IP, and reporter assay for transcriptional regulation; single lab, multiple orthogonal methods","pmids":["31970414"],"is_preprint":false},{"year":2015,"finding":"Dicer interacts with SIRT7 and sequesters a proportion of SIRT7 in the cytoplasm; Dicer knockdown increases chromatin-associated SIRT7 and decreases H3K18Ac, while Dicer overexpression reduces chromatin-associated SIRT7 and increases H3K18Ac levels. DNA damaging agents promote Dicer expression to trap SIRT7 in the cytoplasm.","method":"Co-immunoprecipitation, subcellular fractionation, siRNA/overexpression of Dicer, H3K18Ac immunoblot, DNA damage treatment","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and fractionation with functional H3K18Ac readout; single lab, two orthogonal methods","pmids":["26704979"],"is_preprint":false},{"year":2019,"finding":"SIRT7 promotes chromosome synapsis in female meiosis; Sirt7 KO oocytes show increased unsynapsed chromosomes with elevated H3K18Ac at asynaptic regions, fewer MLH1 crossover foci, and increased aneuploidy in metaphase II eggs.","method":"Sirt7 KO mouse model, immunofluorescence (H3K18Ac, γH2AX, SYCP3, MLH1), aneuploidy assessment, oocyte counting","journal":"Chromosoma","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with multiple meiotic phenotype readouts, H3K18Ac localization at asynaptic regions, and crossover/aneuploidy analysis; multiple orthogonal methods","pmids":["31256246"],"is_preprint":false},{"year":2018,"finding":"SIRT7 is required for spindle organization, cortical actin cap formation, and redox homeostasis during mouse oocyte meiotic maturation; SIRT7 depletion elevates ROS and causes chromosome misalignment and aneuploidy. SIRT7 protein is decreased in oocytes from obese mice, and exogenous SIRT7 rescues obesity-associated meiotic defects.","method":"Specific knockdown in mouse oocytes (morpholino/siRNA), immunofluorescence for spindle/chromosomes/actin, ROS measurement, obesity mouse model rescue experiment","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — oocyte-specific KD with multiple cellular phenotype readouts, ROS assay, and rescue experiment; multiple orthogonal methods","pmids":["29879377"],"is_preprint":false},{"year":2018,"finding":"SIRT7 protects against rDNA instability-induced senescence in human primary cells by promoting association of the chromatin remodeler SNF2H with rDNA sequences; SIRT7-deficient cells show rDNA copy loss and acute senescence.","method":"ChIP for SNF2H at rDNA, rDNA copy number assay, SIRT7 depletion in primary human cells, senescence assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for SNF2H recruitment, functional rDNA instability and senescence assay; single lab, two orthogonal methods","pmids":["29728458"],"is_preprint":false}],"current_model":"SIRT7 is a nucleolus-enriched, NAD+-dependent protein deacylase (deacetylase and defatty-acylase) whose catalytic activity is stimulated by RNA (especially rRNA) and DNA; it deacetylates a diverse set of substrates including histone H3K18Ac, p53, ATM, GABPβ1, SMAD4, FKBP51, CDK9, DDX21, FBL, U3-55k, NPM, CRY1, IGF2BP2, FAM134B, KLF4, and others, thereby regulating Pol I and Pol II transcription, ribosome biogenesis and pre-rRNA processing, DNA double-strand break repair and ATM deactivation, R-loop resolution, heterochromatin maintenance, mitochondrial gene expression, circadian rhythmicity, ER stress, TGF-β/EMT signaling, Hippo/YAP signaling, Akt activity, meiosis, and metabolic homeostasis; its activity is in turn modulated by PRMT6-mediated R388 methylation, USP7-mediated K63-linked deubiquitination, O-GlcNAcylation at S136, ATR-mediated phosphorylation, HDAC8/SMAD3/4-dependent transcriptional repression, and interactions with Dicer and Lamin A/C, placing SIRT7 as a multi-substrate chromatin and signaling nexus that integrates metabolic, genotoxic, and developmental cues."},"narrative":{"mechanistic_narrative":"SIRT7 is a nucleolus-enriched, NAD+-dependent protein deacylase that integrates metabolic, genotoxic, and developmental signals at chromatin to control transcription, ribosome biogenesis, and genome stability [PMID:16618798, PMID:22722849, PMID:27997115]. Its catalytic efficiency is strongly stimulated by nucleic acids—rRNA even more potently than DNA—and it removes not only acetyl but also long-chain fatty-acyl groups from lysines, with subsequent work extending its repertoire to decrotonylation and desuccinylation [PMID:26907567, PMID:27997115, PMID:34604215, PMID:39002692]. In the nucleolus SIRT7 associates with active rDNA and RNA Pol I to drive rRNA transcription, deacetylates the U3 snoRNP component U3-55k to license pre-rRNA processing, and deacetylates fibrillarin to sustain H2AQ104 methylation and Pol I output, while also stabilizing rDNA heterochromatin through recruitment of DNMT1, SIRT1, and SNF2H [PMID:16618798, PMID:26867678, PMID:30540930, PMID:28842251, PMID:29728458]. As an H3K18Ac deacetylase it is targeted to specific promoters by transcription factors including ELK4 and Myc to repress tumor-suppressive and ribosomal-protein genes, and it silences LINE-1 retrotransposons and maintains peripheral heterochromatin via interaction with Lamin A/C and HP1, restraining cGAS-STING innate immune activation [PMID:22722849, PMID:24210820, PMID:31226208, PMID:32504224]. SIRT7 enforces genome integrity by deacetylating H3K18Ac at double-strand breaks to promote 53BP1 recruitment and NHEJ, deacetylating the DDX21 helicase to resolve R-loops, and deacetylating ATM to permit its WIP1-mediated deactivation during recovery from DNA damage [PMID:27225932, PMID:28790157, PMID:30944854]. Beyond chromatin, SIRT7 deacetylation governs the stability or activity of numerous substrates—stabilizing p53 indirectly through NPM, promoting SMAD4 and MST1 degradation to modulate TGF-β/EMT and Hippo/YAP signaling, controlling Akt activity via FKBP51, activating Pol II elongation by deacetylating CDK9, and regulating mitochondrial gene expression through GABPβ1—thereby linking it to apoptosis, metastasis, and metabolic homeostasis [PMID:18239138, PMID:33495326, PMID:28827661, PMID:38288904, PMID:28147277, PMID:28426094, PMID:25200183]. SIRT7 also restrains a second sirtuin by limiting SIRT1 autodeacetylation, and its own function is tuned by PRMT6-mediated R388 methylation, USP7-mediated K63 deubiquitination, OGT-mediated S136 O-GlcNAcylation, ATR phosphorylation, and HDAC8/SMAD3-4-dependent transcriptional repression, as well as cytoplasmic sequestration by Dicer [PMID:28923965, PMID:30420520, PMID:28655758, PMID:35422493, PMID:33495326, PMID:31970414, PMID:26704979].","teleology":[{"year":2006,"claim":"Established SIRT7's foundational role by placing it in the nucleolus as a positive regulator of RNA Pol I transcription, answering where it acts and what process it controls.","evidence":"Co-IP with Pol I, ChIP at rDNA, knockdown/overexpression transcription assays","pmids":["16618798"],"confidence":"High","gaps":["Did not define the catalytic substrate driving Pol I regulation","Mechanism of nucleolar targeting unresolved"]},{"year":2008,"claim":"Identified the first SIRT7 deacetylation substrate, p53, and linked SIRT7 to suppression of apoptosis, showing it acts beyond rDNA transcription.","evidence":"In vitro deacetylation assay and Sirt7 knockout mouse with cardiac p53 hyperacetylation","pmids":["18239138"],"confidence":"High","gaps":["Direct versus indirect deacetylation of p53 not fully separated from later NPM-mediated mechanism","Specific p53 lysines not mapped"]},{"year":2012,"claim":"Defined SIRT7 as a selective H3K18Ac deacetylase recruited by ELK4 to repress tumor-suppressor promoters, establishing its chromatin-modifying activity and oncogenic role.","evidence":"Genome-wide ChIP-seq, in vitro deacetylation, knockdown, xenograft","pmids":["22722849"],"confidence":"High","gaps":["Generality of H3K18Ac specificity across loci not exhaustive","Catalytic activation requirement not yet known"]},{"year":2013,"claim":"Mapped the sequence determinants of SIRT7 nuclear/nucleolar localization and revealed a cytoplasmic pool, addressing how its spatial distribution is controlled and linking nucleolar loss to senescence.","evidence":"Deletion/mutagenesis constructs, fractionation, immunocytochemistry; plus Myc-directed H3K18Ac deacetylation at ribosomal protein genes in a KO mouse","pmids":["23680022","24210820"],"confidence":"High","gaps":["Trigger for cytoplasmic redistribution not defined here","Functional role of cytoplasmic pool unclear"]},{"year":2014,"claim":"Extended SIRT7 substrates to GABPβ1 and showed it controls an E3 ligase (DCAF1/DDB1/CUL4B) to stabilize TR4, connecting it to mitochondrial gene expression and hepatic lipid metabolism.","evidence":"In vitro deacetylation, co-IP, ubiquitination assays, whole-body and liver-specific KO mice","pmids":["25200183","24703702"],"confidence":"High","gaps":["Whether ligase inhibition is deacetylation-dependent not fully resolved in the GABPβ1/TR4 arms","Tissue specificity of substrate selection unclear"]},{"year":2016,"claim":"Defined the biochemical basis of SIRT7 catalysis, showing RNA (especially rRNA) and DNA activate its deacylase activity and that it is an efficient defatty-acylase, answering how a weak deacetylase achieves activity in vivo.","evidence":"In vitro deacylase/defatty-acylase assays with DNA and RNA, RIP-seq, mutagenesis, metabolic labeling","pmids":["26907567","27997115"],"confidence":"High","gaps":["Physiological balance between deacetylase and defatty-acylase functions unresolved","Structural mechanism of nucleic-acid activation not determined"]},{"year":2016,"claim":"Connected SIRT7 deacetylation to pre-rRNA processing (U3-55k) and to DNA double-strand break repair (PARP1-dependent recruitment, 53BP1, NHEJ), establishing dual nucleolar and genome-protective functions.","evidence":"In vitro deacetylation, RIP, rRNA processing assays, ChIP at DSBs, NHEJ assay, progeroid KO mouse","pmids":["26867678","27225932"],"confidence":"High","gaps":["How SIRT7 partitions between rRNA processing and DSB repair not defined","Choice between NHEJ and HR pathways unaddressed"]},{"year":2017,"claim":"Greatly expanded the SIRT7 substrate network—DDX21 (R-loop resolution), SMAD4 (TGF-β/EMT), CDK9 (Pol II elongation), FKBP51 (Akt), FBL, and a SIRT1-restricting role—revealing SIRT7 as a multi-pathway signaling deacetylase.","evidence":"In vitro deacetylation, helicase assays, ubiquitination assays, mutagenesis, ChIP, KO mice and epistasis","pmids":["28790157","28827661","28426094","28147277","28923965"],"confidence":"High","gaps":["Combinatorial logic governing substrate choice unknown","Relative in vivo contribution of each substrate unquantified"]},{"year":2017,"claim":"Established multiple layers of SIRT7 regulation and target circuits—USP7 K63-deubiquitination represses activity, HDAC8/SMAD3-4 repress SIRT7 transcription, and SIRT7 maintains rDNA heterochromatin via DNMT1/SIRT1—showing SIRT7 sits in feedback loops.","evidence":"In vitro deubiquitination/deacetylation, ChIP, reporter assays, bisulfite sequencing, KO cells/mice","pmids":["28655758","31970414","28842251"],"confidence":"High","gaps":["How K63 deubiquitination mechanistically represses catalysis unknown","Interplay between the repressive and activating inputs not integrated"]},{"year":2018,"claim":"Identified PRMT6-mediated R388 methylation as a glucose- and AMPK-responsive switch on SIRT7 activity and connected SIRT7 to FBL/H2AQ104me-dependent Pol I control and rDNA-stability-dependent senescence, coupling metabolism to ribosome biogenesis.","evidence":"In vitro methylation/deacetylation assays, mutagenesis, AMPK activation, ChIP, rDNA copy and senescence assays","pmids":["30420520","30540930","29728458"],"confidence":"High","gaps":["Whether other PTMs cooperate with R388 methylation unresolved","SNF2H recruitment mechanism (29728458, Medium) not biochemically reconstituted"]},{"year":2019,"claim":"Defined SIRT7's role in ATM deactivation, LINE-1 silencing via Lamin A/C, CRY1-dependent circadian control, and meiotic chromosome synapsis, broadening its functions into DNA-damage recovery, retrotransposon control, the clock, and reproduction.","evidence":"In vitro deacetylation, chromatin fractionation, ChIP-seq, retrotransposition and ubiquitination assays, KO mouse circadian and meiotic phenotypes","pmids":["30944854","31226208","32694864","31256246"],"confidence":"High","gaps":["Substrate(s) underlying meiotic phenotype beyond H3K18Ac unidentified","How a single enzyme coordinates these disparate programs unclear"]},{"year":2020,"claim":"Revealed a novel auto-mono-ADP-ribosyltransferase activity with a distinct active site, plus heterochromatin/cGAS-STING control and stress-driven relocalization (DDB1/CRL4, NPM-p53), showing SIRT7 possesses a second catalytic function and senses genotoxic/nutrient stress through subnuclear redistribution.","evidence":"MS identification of ADP-ribosylation, active-site mutagenesis, co-IP, ATR phosphorylation assay, KO mice with calorie restriction or UV","pmids":["32832656","32504224","32404984","33495326","28886238"],"confidence":"High","gaps":["Physiological substrates of the mADPRT activity beyond auto-modification unknown","Coordination of relocalization signals across stresses not unified"]},{"year":2022,"claim":"Identified additional post-translational control (OGT S136 O-GlcNAcylation blocking REGγ-mediated degradation) and metabolic substrates (IGF2BP2/Ucp1, PPARγ2), connecting SIRT7 stability and activity to nutrient signaling and adipose/thermogenic physiology.","evidence":"MS modification mapping, site mutants, co-IP, translation assays, tissue-specific KO mice, xenograft","pmids":["35422493","36509749","33955199"],"confidence":"High","gaps":["Crosstalk between O-GlcNAcylation, methylation, and ubiquitination not resolved","Tissue-specific determinants of substrate choice unknown"]},{"year":2024,"claim":"Extended SIRT7's acyl-removing repertoire (decrotonylation of PHF5A, desuccinylation of KIF23 and histone H3K122) and added KLF4, MST1/Hippo-YAP, DDX3X, and FAM134B/ER-phagy substrates, showing SIRT7 acts on multiple acyl marks across diverse disease contexts.","evidence":"MS, site-specific mutants, ubiquitination/deacylation assays, ChIP, tissue-specific KO and xenograft models","pmids":["34604215","38360598","39002692","38198357","38288904","38277756","37043189"],"confidence":"Medium","gaps":["Several desuccinylation/decrotonylation activities (Medium) lack in vitro reconstitution","Whether non-acetyl acyl removals are physiologically dominant unclear"]},{"year":null,"claim":"How SIRT7's single catalytic core is directed among its many substrates and two enzymatic activities, and how the converging metabolic, genotoxic, and developmental inputs are integrated into substrate-specific outcomes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for substrate selectivity","Relative in vivo weighting of deacetylase versus defatty-acylase versus mADPRT activities undetermined","Structural basis of nucleic-acid-activated catalysis not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,5,9,12,13,14,15,20,23,29,30,33,35,36,37,39,40]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[10]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9,11]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[10]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,16,17]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,3,9,19]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,8,24]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[19,30]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,42]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[8,23]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,4,14]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8,12,23]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[9,20]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,18,24,27]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,6,22,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,15,36]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[25]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[27]}],"complexes":[],"partners":["ELK4","MYC","DDX21","ATM","SMAD4","CDK9","SIRT1","LAMIN A/C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NRC8","full_name":"NAD-dependent protein deacetylase sirtuin-7","aliases":["NAD-dependent protein deacylase sirtuin-7","Regulatory protein SIR2 homolog 7","SIR2-like protein 7"],"length_aa":400,"mass_kda":44.9,"function":"NAD-dependent protein-lysine deacylase that can act both as a deacetylase or deacylase (desuccinylase, depropionylase, deglutarylase and dedecanoylase), depending on the context (PubMed:22722849, PubMed:26907567, PubMed:30653310, PubMed:31542297, PubMed:35939806). Specifically mediates deacetylation of histone H3 at 'Lys-18' (H3K18Ac) (PubMed:22722849, PubMed:30420520, PubMed:35939806). In contrast to other histone deacetylases, displays strong preference for a specific histone mark, H3K18Ac, directly linked to control of gene expression (PubMed:22722849, PubMed:30653310). H3K18Ac is mainly present around the transcription start site of genes and has been linked to activation of nuclear hormone receptors; SIRT7 thereby acts as a transcription repressor (PubMed:22722849). Moreover, H3K18 hypoacetylation has been reported as a marker of malignancy in various cancers and seems to maintain the transformed phenotype of cancer cells (PubMed:22722849). Also able to mediate deacetylation of histone H3 at 'Lys-36' (H3K36Ac) in the context of nucleosomes (PubMed:30653310). Also mediates deacetylation of non-histone proteins, such as ATM, CDK9, DDX21, DDB1, FBL, FKBP5/FKBP51, GABPB1, RAN, RRP9/U3-55K and POLR1E/PAF53 (PubMed:24207024, PubMed:26867678, PubMed:28147277, PubMed:28426094, PubMed:28790157, PubMed:28886238, PubMed:30540930, PubMed:30944854, PubMed:31075303). Enriched in nucleolus where it stimulates transcription activity of the RNA polymerase I complex (PubMed:16618798, PubMed:19174463, PubMed:24207024). Acts by mediating the deacetylation of the RNA polymerase I subunit POLR1E/PAF53, thereby promoting the association of RNA polymerase I with the rDNA promoter region and coding region (PubMed:16618798, PubMed:19174463, PubMed:24207024). In response to metabolic stress, SIRT7 is released from nucleoli leading to hyperacetylation of POLR1E/PAF53 and decreased RNA polymerase I transcription (PubMed:24207024). Required to restore the transcription of ribosomal RNA (rRNA) at the exit from mitosis (PubMed:19174463). Promotes pre-ribosomal RNA (pre-rRNA) cleavage at the 5'-terminal processing site by mediating deacetylation of RRP9/U3-55K, a core subunit of the U3 snoRNP complex (PubMed:26867678). Mediates 'Lys-37' deacetylation of Ran, thereby regulating the nuclear export of NF-kappa-B subunit RELA/p65 (PubMed:31075303). Acts as a regulator of DNA damage repair by mediating deacetylation of ATM during the late stages of DNA damage response, promoting ATM dephosphorylation and deactivation (PubMed:30944854). Suppresses the activity of the DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes by mediating deacetylation of DDB1, which prevents the interaction between DDB1 and CUL4 (CUL4A or CUL4B) (PubMed:28886238). Activates RNA polymerase II transcription by mediating deacetylation of CDK9, thereby promoting 'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (PubMed:28426094). Deacetylates FBL, promoting histone-glutamine methyltransferase activity of FBL (PubMed:30540930). Acts as a regulator of mitochondrial function by catalyzing deacetylation of GABPB1 (By similarity). Regulates Akt/AKT1 activity by mediating deacetylation of FKBP5/FKBP51 (PubMed:28147277). Required to prevent R-loop-associated DNA damage and transcription-associated genomic instability by mediating deacetylation and subsequent activation of DDX21, thereby overcoming R-loop-mediated stalling of RNA polymerases (PubMed:28790157). In addition to protein deacetylase activity, also acts as a protein-lysine deacylase (PubMed:27436229, PubMed:27997115, PubMed:31542297). Acts as a protein depropionylase by mediating depropionylation of Osterix (SP7), thereby regulating bone formation by osteoblasts (By similarity). Acts as a histone deglutarylase by mediating deglutarylation of histone H4 on 'Lys-91' (H4K91glu); a mark that destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes (PubMed:31542297). Acts as a histone desuccinylase: in response to DNA damage, recruited to DNA double-strand breaks (DSBs) and catalyzes desuccinylation of histone H3 on 'Lys-122' (H3K122succ), thereby promoting chromatin condensation and DSB repair (PubMed:27436229). Also promotes DSB repair by promoting H3K18Ac deacetylation, regulating non-homologous end joining (NHEJ) (By similarity). Along with its role in DNA repair, required for chromosome synapsis during prophase I of female meiosis by catalyzing H3K18Ac deacetylation (By similarity). Involved in transcriptional repression of LINE-1 retrotransposon via H3K18Ac deacetylation, and promotes their association with the nuclear lamina (PubMed:31226208). Required to stabilize ribosomal DNA (rDNA) heterochromatin and prevent cellular senescence induced by rDNA instability (PubMed:29728458). Acts as a negative regulator of SIRT1 by preventing autodeacetylation of SIRT1, restricting SIRT1 deacetylase activity (By similarity)","subcellular_location":"Nucleus, nucleolus; Nucleus, nucleoplasm; Chromosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9NRC8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIRT7","classification":"Not Classified","n_dependent_lines":51,"n_total_lines":1208,"dependency_fraction":0.042218543046357616},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SIRT7","total_profiled":1310},"omim":[{"mim_id":"606212","title":"SIRTUIN 7; SIRT7","url":"https://www.omim.org/entry/606212"},{"mim_id":"606211","title":"SIRTUIN 6; SIRT6","url":"https://www.omim.org/entry/606211"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SIRT7"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9NRC8","domains":[{"cath_id":"-","chopping":"11-35_42-73","consensus_level":"high","plddt":93.2312,"start":11,"end":73},{"cath_id":"3.40.50.1220","chopping":"81-341","consensus_level":"high","plddt":94.7967,"start":81,"end":341}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRC8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRC8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRC8-F1-predicted_aligned_error_v6.png","plddt_mean":88.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIRT7","jax_strain_url":"https://www.jax.org/strain/search?query=SIRT7"},"sequence":{"accession":"Q9NRC8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRC8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRC8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRC8"}},"corpus_meta":[{"pmid":"18239138","id":"PMC_18239138","title":"Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice.","date":"2008","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/18239138","citation_count":523,"is_preprint":false},{"pmid":"22722849","id":"PMC_22722849","title":"SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22722849","citation_count":502,"is_preprint":false},{"pmid":"16618798","id":"PMC_16618798","title":"Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription.","date":"2006","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/16618798","citation_count":479,"is_preprint":false},{"pmid":"24210820","id":"PMC_24210820","title":"SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24210820","citation_count":237,"is_preprint":false},{"pmid":"25200183","id":"PMC_25200183","title":"A SIRT7-dependent acetylation switch of GABPβ1 controls mitochondrial function.","date":"2014","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25200183","citation_count":222,"is_preprint":false},{"pmid":"27225932","id":"PMC_27225932","title":"SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair.","date":"2016","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/27225932","citation_count":220,"is_preprint":false},{"pmid":"28790157","id":"PMC_28790157","title":"SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability.","date":"2017","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/28790157","citation_count":198,"is_preprint":false},{"pmid":"28827661","id":"PMC_28827661","title":"SIRT7 antagonizes TGF-β 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Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38779758","citation_count":20,"is_preprint":false},{"pmid":"37957720","id":"PMC_37957720","title":"USP39 interacts with SIRT7 to promote cervical squamous cell carcinoma by modulating autophagy and oxidative stress via FOXM1.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37957720","citation_count":20,"is_preprint":false},{"pmid":"34797559","id":"PMC_34797559","title":"SIRT7 interacts with TEK (TIE2) to promote adriamycin induced metastasis in breast cancer.","date":"2021","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/34797559","citation_count":20,"is_preprint":false},{"pmid":"26704017","id":"PMC_26704017","title":"C/EBPα negatively regulates SIRT7 expression via recruiting HDAC3 to the upstream-promoter of hepatocellular carcinoma cells.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26704017","citation_count":20,"is_preprint":false},{"pmid":"28886238","id":"PMC_28886238","title":"SIRT7 deacetylates DDB1 and suppresses the activity of the CRL4 E3 ligase complexes.","date":"2017","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/28886238","citation_count":19,"is_preprint":false},{"pmid":"29402405","id":"PMC_29402405","title":"SIRT7 is an important regulator of cartilage homeostasis and osteoarthritis development.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29402405","citation_count":19,"is_preprint":false},{"pmid":"36804620","id":"PMC_36804620","title":"Oncogenic SIRT7 inhibits GATA4 transcriptional activity and activates the Wnt signaling pathway in ovarian cancer.","date":"2023","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36804620","citation_count":18,"is_preprint":false},{"pmid":"28556401","id":"PMC_28556401","title":"Quantitative proteome-based systematic identification of SIRT7 substrates.","date":"2017","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/28556401","citation_count":18,"is_preprint":false},{"pmid":"36040642","id":"PMC_36040642","title":"USP17L2-SIRT7 axis regulates DNA damage repair and chemoresistance in breast cancer cells.","date":"2022","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/36040642","citation_count":17,"is_preprint":false},{"pmid":"39002692","id":"PMC_39002692","title":"SIRT7 knockdown promotes gemcitabine sensitivity of pancreatic cancer cell via upregulation of GLUT3 expression.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/39002692","citation_count":16,"is_preprint":false},{"pmid":"35902730","id":"PMC_35902730","title":"CYP2E1-dependent upregulation of SIRT7 is response to alcohol mediated metastasis in hepatocellular carcinoma.","date":"2022","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35902730","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50633,"output_tokens":11760,"usd":0.16415,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22537,"output_tokens":5863,"usd":0.12963,"stage2_stop_reason":"end_turn"},"total_usd":0.29378,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"SIRT7 localizes to the nucleolus, associates with active rRNA genes (rDNA), interacts with RNA Polymerase I and histones, and positively regulates Pol I-mediated transcription; knockdown reduces Pol I association with rDNA and decreases rRNA transcription, while overexpression increases it.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, overexpression with transcription assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, ChIP, and functional transcription assays in the same study; independently referenced by many subsequent papers\",\n      \"pmids\": [\"16618798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SIRT7 interacts with p53 and deacetylates p53 in vitro; Sirt7 knockout mice show hyperacetylation of p53 in vivo and increased cardiomyocyte apoptosis, indicating SIRT7 suppresses p53-dependent apoptosis in the heart.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, Sirt7 knockout mouse model, immunoblot for acetylated p53\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro deacetylation confirmed plus in vivo knockout with acetylation phenotype; independently replicated in later studies\",\n      \"pmids\": [\"18239138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SIRT7 is an NAD+-dependent H3K18Ac deacetylase that binds promoters of tumor-suppressive genes through interaction with the ETS transcription factor ELK4, deacetylates H3K18Ac to repress transcription, and is necessary for maintaining cancer cell transformation and global H3K18Ac hypoacetylation.\",\n      \"method\": \"Genome-wide ChIP-seq, in vitro deacetylation assay, siRNA knockdown, xenograft mouse model, co-immunoprecipitation with ELK4\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deacetylase assay plus genome-wide binding, functional knockout, and in vivo xenograft; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"22722849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SIRT7 nuclear/nucleolar localization is governed by two distinct N-terminal (aa 61-76) and C-terminal (aa 392-400) sequence elements; a cytoplasmic pool of SIRT7 also exists, and loss of nucleolar SIRT7 associates with replicative senescence.\",\n      \"method\": \"Deletion constructs, site-directed mutagenesis, immunocytochemistry, subcellular fractionation, RNAi, peptide competition assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis combined with fractionation and imaging in multiple cell types; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23680022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SIRT7 functions at chromatin as an NAD+-dependent H3K18Ac deacetylase that interacts with the transcription factor Myc at ribosomal protein gene promoters to silence expression and relieve ER stress; SIRT7-deficient mice develop chronic hepatosteatosis.\",\n      \"method\": \"ChIP, co-immunoprecipitation with Myc, siRNA knockdown, Sirt7 knockout mouse model, pharmacologic ER stress suppression rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, co-IP, KO mouse model with rescue experiments; multiple orthogonal methods\",\n      \"pmids\": [\"24210820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SIRT7 deacetylates GABPβ1 at specific lysine residues in its dimerization domains, facilitating GABPβ1/GABPα complex formation and transcriptional activation of nuclear-encoded mitochondrial genes; Sirt7 deficiency in mice causes multisystemic mitochondrial dysfunction.\",\n      \"method\": \"In vitro deacetylation assay, co-immunoprecipitation, Sirt7 knockout mouse model with mitochondrial functional measurements, rescue with SIRT7 overexpression in patient fibroblasts\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deacetylation assay, co-IP, KO mouse phenotype, and human disease cell rescue; multiple orthogonal methods\",\n      \"pmids\": [\"25200183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SIRT7 binds the DCAF1/DDB1/CUL4B E3 ubiquitin ligase complex and inhibits it from ubiquitinating and degrading the nuclear receptor TR4, thereby upregulating TR4 target genes that promote fatty acid uptake and triglyceride synthesis in liver.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Sirt7 knockout mouse on high-fat diet, liver-specific Sirt7 knockout\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of multi-protein complex, in vivo KO phenotype confirmed in liver-specific KO; multiple orthogonal approaches\",\n      \"pmids\": [\"24703702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SIRT7 directly interacts with SIRT1, representing the first demonstration of direct interaction and functional interplay between two mammalian sirtuins; SIRT7 inactivation suppresses metastasis in vivo in both epithelial and mesenchymal cancer models.\",\n      \"method\": \"Co-immunoprecipitation, in vivo metastasis assay, siRNA knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP for interaction, in vivo metastasis suppression; single lab, limited mechanistic depth on the SIRT1 interaction\",\n      \"pmids\": [\"25923013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIRT7 is recruited to DNA double-strand break (DSB) sites in a PARP1-dependent manner, where it deacetylates H3K18Ac to promote 53BP1 recruitment and efficient non-homologous end joining (NHEJ) repair; SIRT7-deficient mice show increased replication stress and a progeroid phenotype.\",\n      \"method\": \"Chromatin immunoprecipitation at DSBs, PARP1 dependency experiments, NHEJ repair assay, SIRT7 knockout mouse model, 53BP1 focal accumulation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at DSB sites, mechanistic PARP1 dependency, NHEJ assay, and in vivo KO phenotype in one study\",\n      \"pmids\": [\"27225932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIRT7 deacetylates U3-55k, a core component of the U3 snoRNP complex; deacetylation enhances U3-55k binding to U3 snoRNA, which is required for pre-rRNA cleavage steps generating 18S rRNA. Under stress, SIRT7 is released from nucleoli, causing hyperacetylation of U3-55k and attenuation of pre-rRNA processing.\",\n      \"method\": \"In vitro deacetylation assay, RNA immunoprecipitation, siRNA knockdown, rRNA processing assays, nucleolar fractionation under stress\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deacetylation assay plus RNA-protein binding assay and functional processing readout; multiple orthogonal methods\",\n      \"pmids\": [\"26867678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DNA activates SIRT7 deacetylase activity in vitro, allowing it to deacetylate H3K18 in the chromatin context; both N- and C-termini are important for this DNA-activated activity, and the mechanism differs from that of SIRT6.\",\n      \"method\": \"In vitro deacetylation assay with DNA, truncation and mutagenesis, chromatin deacetylation assay\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis; single lab but rigorous biochemical approach\",\n      \"pmids\": [\"26907567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RNA (especially rRNA) activates SIRT7 catalytic efficiency even more potently than DNA, and SIRT7 can remove long-chain fatty acyl groups from lysines (defatty-acylase activity) more efficiently than acetyl groups; truncation/mutagenesis identified N- and C-terminal residues involved in RNA binding and activity. RIP-seq identified rRNA as the predominant RNA binding partner.\",\n      \"method\": \"In vitro deacetylase/defatty-acylase assay, RNA immunoprecipitation-sequencing, truncation/mutagenesis, metabolic labeling with alkyne-tagged fatty acid analog\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution plus mutagenesis plus metabolic labeling; multiple orthogonal methods in one study\",\n      \"pmids\": [\"27997115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT7 deacetylates DDX21 (a DEAD-box helicase); deacetylation by SIRT7 augments DDX21 helicase activity to unwind R-loops, while acetylation by CBP inhibits DDX21. Knockdown of SIRT7 phenocopies DDX21 depletion, causing R-loop accumulation and DNA double-strand breaks.\",\n      \"method\": \"In vitro helicase/deacetylation assay, siRNA knockdown, R-loop detection (S9.6 antibody), DNA damage assay, co-immunoprecipitation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deacetylation assay, in vitro helicase activity, genetic epistasis via dual knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"28790157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT7 deacetylates SMAD4, promoting its degradation via β-TrCP1-mediated ubiquitination; SIRT7 deficiency stabilizes SMAD4, activates TGF-β signaling, and enhances epithelial-to-mesenchymal transition and breast cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, ubiquitination assay, siRNA/shRNA knockdown, in vivo metastasis mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deacetylation, ubiquitination assay, co-IP, and in vivo metastasis suppression; multiple orthogonal methods\",\n      \"pmids\": [\"28827661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT7 deacetylates CDK9 (a subunit of P-TEFb) at lysine 48, counteracting GCN5-directed acetylation; deacetylation promotes P-TEFb release from the inactive 7SK snRNP complex and activates CDK9-mediated CTD phosphorylation and Pol II transcription elongation.\",\n      \"method\": \"Proteomic co-IP, in vitro deacetylation assay, ChIP, Pol II CTD phosphorylation assay, siRNA knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deacetylation assay, identification of acetylation site (K48), P-TEFb release assay, and ChIP; multiple orthogonal methods\",\n      \"pmids\": [\"28426094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT7 deacetylates FKBP51 at K28 and K155, which enhances the interaction of FKBP51 with Akt and PHLPP, leading to Akt dephosphorylation; mutation of both lysines to arginine abolishes SIRT7-mediated Akt dephosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis (K28R/K155R), phospho-Akt immunoblot, siRNA knockdown\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical deacetylation assay with mutagenesis ablation of function; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28147277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sirt7 restricts Sirt1 activity by preventing Sirt1 autodeacetylation; increased Sirt1 activity in Sirt7-/- mice blocks PPARγ and adipocyte differentiation, and reducing Sirt1 activity restores adipogenesis in Sirt7-/- cells.\",\n      \"method\": \"In vitro deacetylation assay, Sirt7 knockout mouse model, Sirt1 activity assays, adipocyte differentiation rescue experiments, genetic epistasis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model, in vitro deacetylation assay, and rescue epistasis experiments; multiple orthogonal methods\",\n      \"pmids\": [\"28923965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP7 interacts with SIRT7 and removes K63-linked polyubiquitin chains from SIRT7; while deubiquitination does not affect SIRT7 stability, it represses SIRT7 enzymatic activity. SIRT7 targets the G6PC gluconeogenic gene promoter through ELK4.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay, ubiquitination linkage analysis, in vitro deacetylation assay, ChIP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical deubiquitination assay, ubiquitin linkage specificity, functional activity assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28655758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sirt7 stabilizes rDNA heterochromatin by recruiting DNA methyltransferase 1 (DNMT1) and Sirt1 to rDNA loci; Sirt7 loss leads to nucleolar fragmentation, rDNA hypomethylation, and histone hyperacetylation at rDNA.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, bisulfite sequencing (rDNA methylation), Sirt7 knockout cells/mice\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and co-IP in KO context; single lab, multiple methods but limited biochemical reconstitution\",\n      \"pmids\": [\"28842251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT7 deacetylates DDB1, reducing DDB1 binding to CUL4 and suppressing CRL4 E3 ubiquitin ligase activity; upon nucleolar stress (actinomycin D or 5-FU), SIRT7 redistributes from nucleolus to nucleoplasm to promote DDB1 deacetylation, leading to accumulation of CRL4 substrates including LATS1 and p73.\",\n      \"method\": \"In vitro deacetylation assay, co-immunoprecipitation, siRNA knockdown, actinomycin D/5-FU nucleolar stress treatment, immunoblot for CRL4 substrates\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical deacetylation assay, co-IP, and functional substrate accumulation with stress-dependent relocalization; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28886238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SIRT7 deacetylates fibrillarin (FBL); hyperacetylation of FBL impairs its interaction with histone H2A and chromatin, compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high rRNA synthesis during interphase; at mitotic onset, hyperacetylation of FBL accompanies loss of H2AQ104me and Pol I repression.\",\n      \"method\": \"In vitro deacetylation assay (CBP acetylates, SIRT7 deacetylates FBL), acetylation-deficient/mimicking FBL mutants, H2AQ104me immunoblot, co-immunoprecipitation, ChIP\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deacetylation assay, mutagenesis, H2A methylation assay, and ChIP; multiple orthogonal methods in one study\",\n      \"pmids\": [\"30540930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRMT6 directly methylates SIRT7 at arginine 388 (R388) in vitro and in vivo, inhibiting its H3K18 deacetylase activity without altering subcellular localization. AMPK disrupts PRMT6-SIRT7 association, causing R388 hypomethylation. High glucose enhances R388 methylation, coupling glucose availability to mitochondria biogenesis via SIRT7.\",\n      \"method\": \"In vitro methylation assay, co-immunoprecipitation, SIRT7 deacetylase activity assay with R388 mutant, AMPK activation experiments, immunoblot in mouse liver\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical methylation assay, site-specific mutagenesis, functional enzymatic assay, and in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"30420520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SIRT7 interacts with and deacetylates PPARγ2 at K382; acetylation-mimicking K382Q mutation impairs lipogenesis gene expression (Srebp1c, Acaca, Fasn, Scd1) and reduces PPARγ2 transcriptional activity in adipocytes.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, site-directed mutagenesis (K382Q and K382R), global gene expression analysis, transcriptional activity assay\",\n      \"journal\": \"Journal of diabetes investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical deacetylation assay with mutagenesis and functional gene expression readout; single lab, multiple methods\",\n      \"pmids\": [\"33955199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT7 interacts with and deacetylates ATM in vitro and in vivo; SIRT7-mediated ATM deacetylation is prerequisite for ATM dephosphorylation by phosphatase WIP1. SIRT7 is mobilized onto chromatin during late stages of DNA damage response to deactivate ATM; SIRT7 depletion or acetylation-mimic ATM mutation causes persistent ATM phosphorylation and impaired DNA repair.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, chromatin fractionation, phospho-ATM immunoblot, acetylation-mimicking ATM mutation, DNA repair assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deacetylation assay, mutagenesis, chromatin recruitment assay, and functional DNA repair readout; multiple orthogonal methods\",\n      \"pmids\": [\"30944854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT7 mediates H3K18 deacetylation-dependent epigenetic repression of LINE-1 (L1) retrotransposons genome-wide; SIRT7 interacts with Lamin A/C to promote L1 association with the nuclear lamina. SIRT7 depletion causes increased L1 expression and retrotransposition.\",\n      \"method\": \"ChIP-seq, siRNA knockdown, L1 retrotransposition assay, co-immunoprecipitation with Lamin A/C, SIRT7 KO mouse and human cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq, co-IP, functional retrotransposition assay in mouse and human cells; multiple orthogonal methods\",\n      \"pmids\": [\"31226208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT7 deacetylates CRY1 and promotes its FBXL3-mediated degradation, thereby regulating the hepatic circadian clock. Body temperature oscillations drive HSP70 expression, which promotes SIRT7 ubiquitination and degradation, establishing a BT-HSP70-SIRT7-CRY1 axis coupling the hepatic clock to the central pacemaker.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, Sirt7 knockout mouse model with circadian phase analysis, ubiquitination assay, CRY1 stability assay\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deacetylation, ubiquitination assay, co-IP, and KO mouse circadian phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"32694864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT7 forms a complex with MEF2D that attenuates MEF2D acetylation and reduces MEF2D-driven PD-L1 expression in hepatocellular carcinoma; IFNG-induced p300 acetylates MEF2D and disrupts the MEF2D-SIRT7 interaction, enabling PD-L1 transcription.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assay, ChIP, dual luciferase reporter, SIRT7 knockout in cell lines and orthotopic mouse model\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, ChIP, reporter assay, and in vivo KO model; multiple orthogonal methods\",\n      \"pmids\": [\"31678303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins to maintain repressive heterochromatin at the nuclear periphery; SIRT7 deficiency leads to loss of heterochromatin, de-repression of LINE1, and activation of innate immune signaling via the cGAS-STING pathway in human mesenchymal stem cells.\",\n      \"method\": \"Co-immunoprecipitation with Lamin and HP1 proteins, ChIP, LINE1 expression assay, cGAS-STING pathway activation assay, SIRT7 KD/KO in hMSCs\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of multi-protein complex, ChIP, functional innate immune activation assay; multiple orthogonal methods\",\n      \"pmids\": [\"32504224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SirT7 exhibits auto-mono-ADP-ribosyltransferase (mADPRT) activity at a previously undefined active site distinct from its deacetylase active site; ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions and regulating gene expression involved in second-messenger signaling and autophagy.\",\n      \"method\": \"Mass spectrometry identification of ADP-ribosylation, site-directed mutagenesis of mADPRT active site, chromatin distribution assay, SirT7 KO mouse with calorie restriction\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical identification of novel activity, mutagenesis, chromatin redistribution assay, and in vivo KO; multiple orthogonal methods\",\n      \"pmids\": [\"32832656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIRT7 directly interacts with and deacetylates PCAF at K720; PCAF deacetylation augments its binding to MDM2 (the p53 E3 ligase), leading to MDM2 degradation, p21 upregulation, and cell-cycle arrest under glucose deprivation conditions.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, MDM2 ubiquitination/degradation assay, p21/p53 immunoblot under glucose deprivation, SIRT7 depletion\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical deacetylation assay, co-IP, and functional MDM2 degradation assay; single lab, multiple methods\",\n      \"pmids\": [\"32404984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIRT7 deacetylates NPM (nucleophosmin); ATR-mediated phosphorylation of SIRT7 upon UV irradiation increases its catalytic activity. Deacetylated NPM relocates to the nucleoplasm and binds MDM2, preventing p53 ubiquitination and degradation, thus stabilizing p53 during genotoxic stress.\",\n      \"method\": \"In vitro deacetylation assay, ATR phosphorylation assay, NPM relocalization assay, co-immunoprecipitation with MDM2, p53 stability assay in vitro and in vivo (KO mouse UV response)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deacetylation, phosphorylation assay, co-IP, and in vivo KO mouse validation; multiple orthogonal methods\",\n      \"pmids\": [\"33495326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Progerin (HGPS mutant Lamin A) interacts with and destabilizes SIRT7; ectopic SIRT7 expression alleviates progerin-induced inflammatory response in vascular endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation of progerin-SIRT7, endothelial cell overexpression, inflammatory marker assay, Tie2-Cre Lmna progerin knock-in mouse model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP interaction plus functional rescue; in vivo mouse model but mechanistic depth of destabilization not fully biochemically dissected\",\n      \"pmids\": [\"32128409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIRT7 decrotonylates PHF5A at K25; this PHF5A decrotonylation contributes to decreased CDK2 expression via retained intron-induced abnormal alternative splicing, thereby accelerating fibroblast senescence.\",\n      \"method\": \"Mass spectrometry identification of crotonylation sites, SIRT7 knockdown/overexpression, immunoblot for Kcr, co-IP, CDK2 splicing analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based substrate identification with functional splicing readout; single lab, limited in vitro biochemical reconstitution of decrotonylation\",\n      \"pmids\": [\"34604215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT7 deacetylates insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), enhancing its inhibitory action on Ucp1 mRNA translation, thereby suppressing UCP1 protein levels and brown adipose tissue thermogenesis; Sirt7 knockout mice have higher body temperature and energy expenditure.\",\n      \"method\": \"Sirt7 whole-body and BAT-specific knockout mice, UCP1 protein immunoblot, in vitro deacetylation assay, Ucp1 mRNA translation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — tissue-specific KO with clear phenotype, biochemical deacetylation assay, and mRNA translation assay; multiple orthogonal methods\",\n      \"pmids\": [\"36509749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"O-GlcNAcylation of SIRT7 at serine 136 (S136) by OGT stabilizes SIRT7 protein by blocking its interaction with the proteasome activator REGγ, preventing SIRT7 degradation; SIRT7 O-GlcNAcylation is required for its H3K18 deacetylase activity and oncogenic function in pancreatic cancer.\",\n      \"method\": \"Mass spectrometry (OGT interaction and S136 modification), co-immunoprecipitation, S136A mutant, H3K18ac immunoblot, in vivo xenograft\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — MS identification of modification site, site-specific mutant, co-IP for REGγ interaction, and functional deacetylase assay; multiple orthogonal methods\",\n      \"pmids\": [\"35422493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT7 deacetylates FAM134B (an ER-phagy receptor), counteracting CBP-mediated acetylation that promotes ER-phagy; SIRT7-mediated deacetylation tempers FAM134B activity to avoid excessive ER degradation, maintaining ER homeostasis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, ER-phagy assay, CBP/SIRT7 gain- and loss-of-function\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical deacetylation assay with co-IP and functional ER-phagy readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37043189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT7 suppresses MST1 (a Hippo pathway kinase) by two mechanisms: (1) binding to the MST1 promoter and inducing H3K18 deacetylation to repress transcription, and (2) directly binding and deacetylating MST1 protein, which primes acetylation-dependent MST1 ubiquitination and degradation; this promotes YAP nuclear localization and activation in hepatocellular carcinoma.\",\n      \"method\": \"ChIP, luciferase reporter assay, co-immunoprecipitation, mass spectrometry (deacetylation), ubiquitination assay, xenograft mouse model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP for transcriptional regulation, co-IP and MS for direct deacetylation, ubiquitination assay, and in vivo xenograft; multiple orthogonal methods\",\n      \"pmids\": [\"38288904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT7 deacetylates KLF4 (Krüppel-like factor 4) at K228, inhibiting its ubiquitination-proteasome degradation; the SIRT7/KLF4 axis maintains pulmonary arterial endothelial cell homeostasis; endothelium-specific SIRT7 depletion exacerbates pulmonary hypertension.\",\n      \"method\": \"Co-immunoprecipitation, deacetylation assay, ubiquitination assay, endothelium-specific Sirt7 KO mouse in SuHx PH model, AAV-mediated SIRT7 overexpression rescue\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deacetylation and ubiquitination assay, tissue-specific KO, and AAV rescue; multiple orthogonal methods\",\n      \"pmids\": [\"38198357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT7 interacts with DDX3X and deacetylates it; SIRT7-mediated DDX3X deacetylation promotes DDX3X protein stability. SIRT7 inhibition leads to DDX3X depletion, disruption of NLRP3 inflammasome assembly, and suppression of ERK1/2 signaling, re-sensitizing cells to sorafenib.\",\n      \"method\": \"Mass spectrometry (DDX3X as SIRT7 target), co-immunoprecipitation, DDX3X deacetylation assay, NLRP3 inflammasome assay, in vivo xenograft with SIRT7 inhibitors\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification plus co-IP and functional pathway assay; single lab, limited biochemical reconstitution depth\",\n      \"pmids\": [\"38277756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT7 directly interacts with KIF23 and catalyzes its desuccinylation at K537, which enhances KIF23 protein stability and promotes anaplastic thyroid cancer cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation, succinylation immunoblot with K537 mutant, SIRT7 overexpression/knockdown, cell viability and migration assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP and site-specific mutagenesis with functional readout; single lab, limited biochemical reconstitution of desuccinylation\",\n      \"pmids\": [\"38360598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT7 directly interacts with the GLUT3 enhancer region and desuccinylates H3K122 at that locus, repressing GLUT3 expression; SIRT7 knockdown upregulates GLUT3 and sensitizes pancreatic cancer cells to gemcitabine.\",\n      \"method\": \"ChIP, co-IP, H3K122 succinylation immunoblot, ATAC-seq/RNA-seq cross-analysis, SIRT7 KD with gemcitabine sensitivity assay, xenograft mouse model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and succinylation immunoblot with functional drug sensitivity readout; single lab, limited in vitro biochemical reconstitution of histone desuccinylation\",\n      \"pmids\": [\"39002692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC8 forms a complex with SMAD3/4 and occupies the SIRT7 promoter, where it deacetylates H4 to transcriptionally suppress SIRT7 expression; this establishes a TGF-β/HDAC8/SMAD3-4/SIRT7 regulatory feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown of HDAC8/SMAD3/4, luciferase reporter assay, H4 acetylation immunoblot at SIRT7 promoter\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-IP, and reporter assay for transcriptional regulation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31970414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Dicer interacts with SIRT7 and sequesters a proportion of SIRT7 in the cytoplasm; Dicer knockdown increases chromatin-associated SIRT7 and decreases H3K18Ac, while Dicer overexpression reduces chromatin-associated SIRT7 and increases H3K18Ac levels. DNA damaging agents promote Dicer expression to trap SIRT7 in the cytoplasm.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, siRNA/overexpression of Dicer, H3K18Ac immunoblot, DNA damage treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and fractionation with functional H3K18Ac readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"26704979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT7 promotes chromosome synapsis in female meiosis; Sirt7 KO oocytes show increased unsynapsed chromosomes with elevated H3K18Ac at asynaptic regions, fewer MLH1 crossover foci, and increased aneuploidy in metaphase II eggs.\",\n      \"method\": \"Sirt7 KO mouse model, immunofluorescence (H3K18Ac, γH2AX, SYCP3, MLH1), aneuploidy assessment, oocyte counting\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with multiple meiotic phenotype readouts, H3K18Ac localization at asynaptic regions, and crossover/aneuploidy analysis; multiple orthogonal methods\",\n      \"pmids\": [\"31256246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SIRT7 is required for spindle organization, cortical actin cap formation, and redox homeostasis during mouse oocyte meiotic maturation; SIRT7 depletion elevates ROS and causes chromosome misalignment and aneuploidy. SIRT7 protein is decreased in oocytes from obese mice, and exogenous SIRT7 rescues obesity-associated meiotic defects.\",\n      \"method\": \"Specific knockdown in mouse oocytes (morpholino/siRNA), immunofluorescence for spindle/chromosomes/actin, ROS measurement, obesity mouse model rescue experiment\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — oocyte-specific KD with multiple cellular phenotype readouts, ROS assay, and rescue experiment; multiple orthogonal methods\",\n      \"pmids\": [\"29879377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SIRT7 protects against rDNA instability-induced senescence in human primary cells by promoting association of the chromatin remodeler SNF2H with rDNA sequences; SIRT7-deficient cells show rDNA copy loss and acute senescence.\",\n      \"method\": \"ChIP for SNF2H at rDNA, rDNA copy number assay, SIRT7 depletion in primary human cells, senescence assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for SNF2H recruitment, functional rDNA instability and senescence assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"29728458\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIRT7 is a nucleolus-enriched, NAD+-dependent protein deacylase (deacetylase and defatty-acylase) whose catalytic activity is stimulated by RNA (especially rRNA) and DNA; it deacetylates a diverse set of substrates including histone H3K18Ac, p53, ATM, GABPβ1, SMAD4, FKBP51, CDK9, DDX21, FBL, U3-55k, NPM, CRY1, IGF2BP2, FAM134B, KLF4, and others, thereby regulating Pol I and Pol II transcription, ribosome biogenesis and pre-rRNA processing, DNA double-strand break repair and ATM deactivation, R-loop resolution, heterochromatin maintenance, mitochondrial gene expression, circadian rhythmicity, ER stress, TGF-β/EMT signaling, Hippo/YAP signaling, Akt activity, meiosis, and metabolic homeostasis; its activity is in turn modulated by PRMT6-mediated R388 methylation, USP7-mediated K63-linked deubiquitination, O-GlcNAcylation at S136, ATR-mediated phosphorylation, HDAC8/SMAD3/4-dependent transcriptional repression, and interactions with Dicer and Lamin A/C, placing SIRT7 as a multi-substrate chromatin and signaling nexus that integrates metabolic, genotoxic, and developmental cues.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIRT7 is a nucleolus-enriched, NAD+-dependent protein deacylase that integrates metabolic, genotoxic, and developmental signals at chromatin to control transcription, ribosome biogenesis, and genome stability [#0, #2, #11]. Its catalytic efficiency is strongly stimulated by nucleic acids—rRNA even more potently than DNA—and it removes not only acetyl but also long-chain fatty-acyl groups from lysines, with subsequent work extending its repertoire to decrotonylation and desuccinylation [#10, #11, #32, #40]. In the nucleolus SIRT7 associates with active rDNA and RNA Pol I to drive rRNA transcription, deacetylates the U3 snoRNP component U3-55k to license pre-rRNA processing, and deacetylates fibrillarin to sustain H2AQ104 methylation and Pol I output, while also stabilizing rDNA heterochromatin through recruitment of DNMT1, SIRT1, and SNF2H [#0, #9, #20, #18, #45]. As an H3K18Ac deacetylase it is targeted to specific promoters by transcription factors including ELK4 and Myc to repress tumor-suppressive and ribosomal-protein genes, and it silences LINE-1 retrotransposons and maintains peripheral heterochromatin via interaction with Lamin A/C and HP1, restraining cGAS-STING innate immune activation [#2, #4, #24, #27]. SIRT7 enforces genome integrity by deacetylating H3K18Ac at double-strand breaks to promote 53BP1 recruitment and NHEJ, deacetylating the DDX21 helicase to resolve R-loops, and deacetylating ATM to permit its WIP1-mediated deactivation during recovery from DNA damage [#8, #12, #23]. Beyond chromatin, SIRT7 deacetylation governs the stability or activity of numerous substrates—stabilizing p53 indirectly through NPM, promoting SMAD4 and MST1 degradation to modulate TGF-β/EMT and Hippo/YAP signaling, controlling Akt activity via FKBP51, activating Pol II elongation by deacetylating CDK9, and regulating mitochondrial gene expression through GABPβ1—thereby linking it to apoptosis, metastasis, and metabolic homeostasis [#1, #30, #13, #36, #15, #14, #5]. SIRT7 also restrains a second sirtuin by limiting SIRT1 autodeacetylation, and its own function is tuned by PRMT6-mediated R388 methylation, USP7-mediated K63 deubiquitination, OGT-mediated S136 O-GlcNAcylation, ATR phosphorylation, and HDAC8/SMAD3-4-dependent transcriptional repression, as well as cytoplasmic sequestration by Dicer [#16, #21, #17, #34, #30, #41, #42].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established SIRT7's foundational role by placing it in the nucleolus as a positive regulator of RNA Pol I transcription, answering where it acts and what process it controls.\",\n      \"evidence\": \"Co-IP with Pol I, ChIP at rDNA, knockdown/overexpression transcription assays\",\n      \"pmids\": [\"16618798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the catalytic substrate driving Pol I regulation\", \"Mechanism of nucleolar targeting unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the first SIRT7 deacetylation substrate, p53, and linked SIRT7 to suppression of apoptosis, showing it acts beyond rDNA transcription.\",\n      \"evidence\": \"In vitro deacetylation assay and Sirt7 knockout mouse with cardiac p53 hyperacetylation\",\n      \"pmids\": [\"18239138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect deacetylation of p53 not fully separated from later NPM-mediated mechanism\", \"Specific p53 lysines not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined SIRT7 as a selective H3K18Ac deacetylase recruited by ELK4 to repress tumor-suppressor promoters, establishing its chromatin-modifying activity and oncogenic role.\",\n      \"evidence\": \"Genome-wide ChIP-seq, in vitro deacetylation, knockdown, xenograft\",\n      \"pmids\": [\"22722849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of H3K18Ac specificity across loci not exhaustive\", \"Catalytic activation requirement not yet known\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped the sequence determinants of SIRT7 nuclear/nucleolar localization and revealed a cytoplasmic pool, addressing how its spatial distribution is controlled and linking nucleolar loss to senescence.\",\n      \"evidence\": \"Deletion/mutagenesis constructs, fractionation, immunocytochemistry; plus Myc-directed H3K18Ac deacetylation at ribosomal protein genes in a KO mouse\",\n      \"pmids\": [\"23680022\", \"24210820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for cytoplasmic redistribution not defined here\", \"Functional role of cytoplasmic pool unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended SIRT7 substrates to GABPβ1 and showed it controls an E3 ligase (DCAF1/DDB1/CUL4B) to stabilize TR4, connecting it to mitochondrial gene expression and hepatic lipid metabolism.\",\n      \"evidence\": \"In vitro deacetylation, co-IP, ubiquitination assays, whole-body and liver-specific KO mice\",\n      \"pmids\": [\"25200183\", \"24703702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ligase inhibition is deacetylation-dependent not fully resolved in the GABPβ1/TR4 arms\", \"Tissue specificity of substrate selection unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the biochemical basis of SIRT7 catalysis, showing RNA (especially rRNA) and DNA activate its deacylase activity and that it is an efficient defatty-acylase, answering how a weak deacetylase achieves activity in vivo.\",\n      \"evidence\": \"In vitro deacylase/defatty-acylase assays with DNA and RNA, RIP-seq, mutagenesis, metabolic labeling\",\n      \"pmids\": [\"26907567\", \"27997115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological balance between deacetylase and defatty-acylase functions unresolved\", \"Structural mechanism of nucleic-acid activation not determined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected SIRT7 deacetylation to pre-rRNA processing (U3-55k) and to DNA double-strand break repair (PARP1-dependent recruitment, 53BP1, NHEJ), establishing dual nucleolar and genome-protective functions.\",\n      \"evidence\": \"In vitro deacetylation, RIP, rRNA processing assays, ChIP at DSBs, NHEJ assay, progeroid KO mouse\",\n      \"pmids\": [\"26867678\", \"27225932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SIRT7 partitions between rRNA processing and DSB repair not defined\", \"Choice between NHEJ and HR pathways unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Greatly expanded the SIRT7 substrate network—DDX21 (R-loop resolution), SMAD4 (TGF-β/EMT), CDK9 (Pol II elongation), FKBP51 (Akt), FBL, and a SIRT1-restricting role—revealing SIRT7 as a multi-pathway signaling deacetylase.\",\n      \"evidence\": \"In vitro deacetylation, helicase assays, ubiquitination assays, mutagenesis, ChIP, KO mice and epistasis\",\n      \"pmids\": [\"28790157\", \"28827661\", \"28426094\", \"28147277\", \"28923965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial logic governing substrate choice unknown\", \"Relative in vivo contribution of each substrate unquantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established multiple layers of SIRT7 regulation and target circuits—USP7 K63-deubiquitination represses activity, HDAC8/SMAD3-4 repress SIRT7 transcription, and SIRT7 maintains rDNA heterochromatin via DNMT1/SIRT1—showing SIRT7 sits in feedback loops.\",\n      \"evidence\": \"In vitro deubiquitination/deacetylation, ChIP, reporter assays, bisulfite sequencing, KO cells/mice\",\n      \"pmids\": [\"28655758\", \"31970414\", \"28842251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How K63 deubiquitination mechanistically represses catalysis unknown\", \"Interplay between the repressive and activating inputs not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified PRMT6-mediated R388 methylation as a glucose- and AMPK-responsive switch on SIRT7 activity and connected SIRT7 to FBL/H2AQ104me-dependent Pol I control and rDNA-stability-dependent senescence, coupling metabolism to ribosome biogenesis.\",\n      \"evidence\": \"In vitro methylation/deacetylation assays, mutagenesis, AMPK activation, ChIP, rDNA copy and senescence assays\",\n      \"pmids\": [\"30420520\", \"30540930\", \"29728458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other PTMs cooperate with R388 methylation unresolved\", \"SNF2H recruitment mechanism (29728458, Medium) not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined SIRT7's role in ATM deactivation, LINE-1 silencing via Lamin A/C, CRY1-dependent circadian control, and meiotic chromosome synapsis, broadening its functions into DNA-damage recovery, retrotransposon control, the clock, and reproduction.\",\n      \"evidence\": \"In vitro deacetylation, chromatin fractionation, ChIP-seq, retrotransposition and ubiquitination assays, KO mouse circadian and meiotic phenotypes\",\n      \"pmids\": [\"30944854\", \"31226208\", \"32694864\", \"31256246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate(s) underlying meiotic phenotype beyond H3K18Ac unidentified\", \"How a single enzyme coordinates these disparate programs unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a novel auto-mono-ADP-ribosyltransferase activity with a distinct active site, plus heterochromatin/cGAS-STING control and stress-driven relocalization (DDB1/CRL4, NPM-p53), showing SIRT7 possesses a second catalytic function and senses genotoxic/nutrient stress through subnuclear redistribution.\",\n      \"evidence\": \"MS identification of ADP-ribosylation, active-site mutagenesis, co-IP, ATR phosphorylation assay, KO mice with calorie restriction or UV\",\n      \"pmids\": [\"32832656\", \"32504224\", \"32404984\", \"33495326\", \"28886238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates of the mADPRT activity beyond auto-modification unknown\", \"Coordination of relocalization signals across stresses not unified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified additional post-translational control (OGT S136 O-GlcNAcylation blocking REGγ-mediated degradation) and metabolic substrates (IGF2BP2/Ucp1, PPARγ2), connecting SIRT7 stability and activity to nutrient signaling and adipose/thermogenic physiology.\",\n      \"evidence\": \"MS modification mapping, site mutants, co-IP, translation assays, tissue-specific KO mice, xenograft\",\n      \"pmids\": [\"35422493\", \"36509749\", \"33955199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between O-GlcNAcylation, methylation, and ubiquitination not resolved\", \"Tissue-specific determinants of substrate choice unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended SIRT7's acyl-removing repertoire (decrotonylation of PHF5A, desuccinylation of KIF23 and histone H3K122) and added KLF4, MST1/Hippo-YAP, DDX3X, and FAM134B/ER-phagy substrates, showing SIRT7 acts on multiple acyl marks across diverse disease contexts.\",\n      \"evidence\": \"MS, site-specific mutants, ubiquitination/deacylation assays, ChIP, tissue-specific KO and xenograft models\",\n      \"pmids\": [\"34604215\", \"38360598\", \"39002692\", \"38198357\", \"38288904\", \"38277756\", \"37043189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several desuccinylation/decrotonylation activities (Medium) lack in vitro reconstitution\", \"Whether non-acetyl acyl removals are physiologically dominant unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SIRT7's single catalytic core is directed among its many substrates and two enzymatic activities, and how the converging metabolic, genotoxic, and developmental inputs are integrated into substrate-specific outcomes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for substrate selectivity\", \"Relative in vivo weighting of deacetylase versus defatty-acylase versus mADPRT activities undetermined\", \"Structural basis of nucleic-acid-activated catalysis not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 5, 9, 12, 13, 14, 15, 20, 23, 29, 30, 33, 35, 36, 37, 39, 40]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 16, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 3, 9, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 8, 24]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [19, 30]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 42]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [8, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 4, 14]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8, 12, 23]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [9, 20]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 18, 24, 27]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 6, 22, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 15, 36]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ELK4\", \"MYC\", \"DDX21\", \"ATM\", \"SMAD4\", \"CDK9\", \"SIRT1\", \"Lamin A/C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}