{"gene":"E2F7","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2003,"finding":"E2F7 contains two DNA-binding domains and binds E2F consensus DNA sites independently of DP co-factors, unlike canonical E2F family members. Ectopic expression of E2F7 suppresses E2F target genes and causes G1 accumulation. E2F7 associates with E2F-regulated promoters in vivo, with increased association during S phase, and represses only a subset of E2F-dependent promoters.","method":"Ectopic expression, ChIP, reporter assays, flow cytometry, sequence analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter assay, flow cytometry, knockdown), replicated in a second independent paper (PMID:12893818) the same year","pmids":["14633988","12893818"],"is_preprint":false},{"year":2003,"finding":"E2F7 protein is localized to the nucleus, associates with DNA E2F recognition sites with high affinity, lacks a dimerization domain, transcriptional activation domain, and retinoblastoma-binding domain. E2F7 blocks E2F-dependent activation of a subset of E2F target genes and reduces cellular proliferation of mouse embryo fibroblasts.","method":"Nuclear fractionation/localization, DNA-binding assays, reporter assays, proliferation assays in MEFs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical assays with functional readout, replicated by PMID:14633988","pmids":["12893818"],"is_preprint":false},{"year":2004,"finding":"E2F7 has two separate DNA-binding domains both required for DNA binding, cell cycle delay, and transcriptional modulation. Mutational analysis shows that integrity of both DBDs is necessary. Biochemical and modeling data suggest E2F7 binds DNA most likely as a homodimer, with interactions between the two DBDs mimicking an E2F/DP heterodimer.","method":"Mutational analysis of DBDs, DNA-binding assays, protein modeling, cell cycle assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis combined with functional and biochemical validation in one study","pmids":["15133492"],"is_preprint":false},{"year":2008,"finding":"E2F7 and E2F8 form homo- and heterodimers that bind E2F target promoters including E2F1. Combined deletion of E2f7 and E2f8 in mice causes massive apoptosis and embryonic lethality by E11.5. Loss of E2F7/8 increases E2F1 and p53 levels; loss of either E2f1 or p53 suppresses the apoptosis in double-mutant embryos, establishing an E2F7/8→E2F1→p53 apoptotic axis.","method":"Conditional knockout mice, ChIP, genetic epistasis (triple mutants), immunoblotting","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with multiple orthogonal methods and full genetic rescue experiments","pmids":["18194653"],"is_preprint":false},{"year":2008,"finding":"E2F7 and E2F8 are induced by DNA-damaging agents and bind the promoter of E2F1 (coexisting in a DNA-binding complex) to repress E2F target genes including E2F1. Depletion of either E2F7 or E2F8 increases E2F1 expression and prevents the cell-cycle effects that occur in response to DNA damage, placing E2F7/8 upstream of E2F1 in the DNA damage response.","method":"ChIP, siRNA knockdown, reporter assays, flow cytometry after DNA damage","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal ChIP and functional knockdown with specific phenotypic readout, replicated direction consistent with PMID:18194653","pmids":["18202719"],"is_preprint":false},{"year":2011,"finding":"E2F7 is highly expressed during mid-to-late S phase, occupies promoters of G1/S-regulated genes (preferentially binding the TTCCCGCC motif), and directly represses their transcription. ChIP-seq identified 89 direct E2F7 target genes involved in DNA replication, metabolism, and DNA repair. Induction of E2F7 during G0-G1/S causes S-phase arrest and DNA damage, whereas expression during G2/M does not disturb cell cycle progression.","method":"ChIP-seq, inducible overexpression, microarray, flow cytometry, comet assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide ChIP-seq plus functional inducible expression system with multiple orthogonal readouts","pmids":["22180533"],"is_preprint":false},{"year":2012,"finding":"In response to DNA damage, p53 directly occupies the E2F7 promoter and transcriptionally up-regulates E2F7. E2F7 in turn occupies the E2F1 and DHFR promoters and represses them; ablation of E2F7 abrogates p53-dependent repression of these targets. This defines a p53→E2F7→E2F1/DHFR repression pathway contributing to DNA damage-induced cell cycle arrest.","method":"ChIP, siRNA knockdown, reporter assays, qPCR, proliferation assays after genotoxic stress","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP for p53 at E2F7 promoter, ChIP for E2F7 at target promoters, functional rescue; independently replicated in PMID:22802529","pmids":["22802528"],"is_preprint":false},{"year":2012,"finding":"E2F7 is the only E2F transcription factor potently up-regulated during oncogene-induced senescence as a direct p53 transcriptional target. Once induced, E2F7 binds and represses E2F target genes and cooperates with RB to enforce cell cycle arrest. When RB is disrupted, E2F7 is further induced and compensates for loss of RB by repressing mitotic E2F target genes, creating a second checkpoint.","method":"Oncogene-induced senescence model, ChIP, shRNA knockdown, epistasis experiments (RB loss), gene expression arrays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus genetic epistasis in relevant biological context; replicated p53→E2F7 axis from PMID:22802528","pmids":["22802529"],"is_preprint":false},{"year":2012,"finding":"E2F7 and E2F8 form a transcriptional complex with HIF1 to stimulate VEGFA promoter activity independent of canonical E2F binding elements, thereby promoting angiogenesis. Simultaneous deletion of E2F7/8 in zebrafish and mice causes severe vascular defects.","method":"Reporter assays, ChIP, genetic knockout in zebrafish and mice, transgenic fluorescent vessel imaging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter, two organism knockout models) establishing a specific molecular mechanism","pmids":["22903062"],"is_preprint":false},{"year":2013,"finding":"E2F7 forms a heterodimer with E2F1 through interactions involving the DNA-binding domains. In vitro DNA interaction assays demonstrate both E2F1-E2F7 and E2F7-E2F7 complexes on adjacent E2F-binding sites. E2F7 recruits the co-repressor CtBP, and CtBP2 is essential for E2F7-mediated repression of E2F1 transcription.","method":"In vitro DNA-binding assays, Co-IP, reporter assays, siRNA knockdown of CtBP2","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution of protein-DNA complexes plus functional co-repressor requirement validated by knockdown","pmids":["23853115"],"is_preprint":false},{"year":2013,"finding":"E2F7 makes a transcription-independent contribution to DNA repair by localizing to and binding damaged DNA, where it recruits CtBP and HDAC to alter the local chromatin environment at DNA lesions. Tumor-derived E2F7 mutant alleles encode proteins with compromised transcription and DNA repair properties.","method":"Laser micro-irradiation/live imaging at damage sites, ChIP at damaged DNA, HDAC/CtBP recruitment assays, mutant allele functional analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — novel finding from single lab with direct localization and recruitment experiments, but abstract-level detail limits full tier assignment","pmids":["23974101"],"is_preprint":false},{"year":2014,"finding":"E2F7 interacts with CtBP1 and CtBP2 through a canonical CtBP-binding motif (PIDLS). CtBP2 proteome analysis confirmed E2F7 as a CtBP2-associated protein. E2F7 represses E2F1 transcription and inhibits cell proliferation in a CtBP-dependent manner; CtBP also participates in E2F7-mediated DNA damage response.","method":"Proteomic analysis (MS) of CtBP2-associated proteins, Co-IP, reporter assays, proliferation assays, mutagenesis of PIDLS motif","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome plus functional validation, single lab","pmids":["24955216"],"is_preprint":false},{"year":2015,"finding":"E2F7 and HIF1α form a transcriptional complex that co-regulates a genome-wide network of genes with both stimulatory and repressive functions. The HIF1α-E2F7 complex represses Neuropilin 1 (NRP1) through a 41 bp E2F-binding site hub, and this repression regulates motor neuron axon guidance in vivo in zebrafish.","method":"ChIP-seq, genome-wide RNA-seq, in vitro reporter assays, in vivo zebrafish morpholino knockdown, TALEN mutagenesis, in situ hybridization","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP-seq plus genome-wide expression analysis with in vivo genetic rescue in two organisms","pmids":["26681691"],"is_preprint":false},{"year":2016,"finding":"E2F7 transcriptionally represses a set of proliferation-promoting microRNAs (miR-25, -26a, -27b, -92a, -7) by antagonizing E2F1-3 at their promoters. Additionally, E2F7 indirectly controls let-7 miRNA processing and maturation through a novel E2F/c-MYC/LIN28B axis, whereby E2F7 and E2F1-3 modulate c-MYC and LIN28B levels.","method":"Genome-wide RNA-seq, ChIP, reporter assays, siRNA knockdown, qPCR","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide approach combined with ChIP and functional validation in a single lab study","pmids":["26961310"],"is_preprint":false},{"year":2017,"finding":"E2F7 binds the p21(CIP1/WAF1) promoter and represses its expression in AML cells, promoting cell cycle progression. Interference with E2F7 expression results in inhibition of c-Myc transcriptional activity and downregulation of the miR-17-92 cluster, which contributes to monocytic differentiation block.","method":"ChIP, reporter assays, siRNA knockdown, flow cytometry, differentiation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct binding to p21 promoter plus functional pathway analysis, single lab","pmids":["23096114"],"is_preprint":false},{"year":2018,"finding":"E2F7 is subject to XPO1 (exportin 1)-dependent nuclear export and is mislocalized to the cytoplasm in >80% of head and neck squamous cell carcinomas (HNSCC). This cytoplasmic mislocalization causes derepression of the E2F7 target SPHK1, driving anthracycline resistance. Treatment with the XPO1 inhibitor selinexor restores nuclear E2F7 and reverses resistance in xenotransplant models.","method":"XPO1 inhibitor treatment, nuclear/cytoplasmic fractionation, IHC of human tumors, ChIP for SPHK1 promoter, xenograft models","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with functional consequence, mechanistic linkage to specific target gene, in vivo validation","pmids":["29950445"],"is_preprint":false},{"year":2018,"finding":"E2F7-mediated transcriptional repression of RAD51 modulates chemosensitivity of BRCA2-deficient cells. Loss of E2F7 increases RAD51 expression, enhances homologous recombination DNA repair and replication fork stability in BRCA2-deficient cells, and confers resistance to PARP inhibitors and cisplatin.","method":"siRNA/shRNA knockdown, ChIP for RAD51 promoter, HR assay, replication fork assay, cell viability assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct E2F7 occupancy at RAD51 promoter, functional HR assay, mechanistic pathway established","pmids":["30032296"],"is_preprint":false},{"year":2018,"finding":"E2F7 represses the expression of genes involved in DNA repair (including RAD51) both throughout the cell cycle and upon induction of DNA interstrand crosslink lesions. E2F7 knockdown reduces 53BP1 and FANCD2 foci, decreases chromosomal aberrations after ICL-inducing agents (but not ionizing radiation), and enhances clonogenic survival after ICL, establishing E2F7 as a restrictor of homologous recombination via RAD51 repression.","method":"siRNA knockdown, immunofluorescence (53BP1/FANCD2 foci), chromosomal aberration analysis, cell-based HR assay, clonogenic survival","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods establishing mechanism, consistent with PMID:30032296 from independent lab","pmids":["29590434"],"is_preprint":false},{"year":2018,"finding":"E2F7 localizes to the perinucleolar region and represses RNA Polymerase I (Pol I) transcription of ribosomal rRNA genes. Mechanistically, E2F7 hinders UBF (upstream binding factor) recruitment to the rRNA gene promoter, thereby reducing rRNA gene transcription and compromising global protein synthesis.","method":"Subcellular localization (immunofluorescence), ChIP at rRNA gene promoter, Pol I transcription assays, protein synthesis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization plus ChIP and functional assay from single lab, novel finding not yet replicated","pmids":["29760477"],"is_preprint":false},{"year":2019,"finding":"E2F7 is targeted for proteasomal degradation by the E3 ubiquitin ligase SCF-Cyclin F during G2 phase. Cyclin F binds via its cyclin domain to a conserved C-terminal CY motif on E2F7. An E2F7 mutant unable to interact with SCF-Cyclin F remains stable during G2. Cyclin F depletion causes atypical-E2F-dependent delay of G2/M transition and reduced expression of DNA repair E2F target genes, impairing efficient DNA repair.","method":"Co-IP, CY motif mutagenesis, cyclin F depletion, live-cell imaging, ubiquitination assays, cell cycle analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis of degron motif, biochemical interaction, functional consequence with live imaging, multiple orthogonal methods in single rigorous study","pmids":["31475738"],"is_preprint":false},{"year":2009,"finding":"E2F7-mediated suppression of proliferation and apoptosis in keratinocytes acts through E2F1-dependent pathways, whereas E2F7-induced differentiation acts through an E2F1-independent pathway. Inhibition of E2F7 in SCC cells sensitizes them to UV- and doxorubicin-induced apoptosis.","method":"Ectopic expression, siRNA knockdown, proliferation/apoptosis assays, differentiation marker assays in primary human keratinocytes","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis between E2F7 and E2F1 established by double-manipulation experiments with multiple phenotypic readouts","pmids":["19223542"],"is_preprint":false},{"year":2011,"finding":"E2F7 binds to a unique binding site between -139 and -119 bp of the Sp1 promoter in differentiating keratinocytes. Knockdown of E2F7 in proliferating keratinocytes leads to derepression of Sp1 expression and induction of the differentiation gene TG1. E2F4 knockdown does not alter Sp1 expression, indicating E2F7-specific regulation.","method":"ChIP, transient transfection, shRNA knockdown, reporter assays with deletion mapping","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assays with functional knockdown, single lab, clear mechanistic dissection","pmids":["21248772"],"is_preprint":false},{"year":2015,"finding":"E2F7 competes with E2F1 for binding at the E2F binding site on the miR-15a/16 host gene DLEU2 promoter. Overexpression of E2F7 represses miR-15a/16, leading to increased Cyclin E1 and Bcl-2 and conferring tamoxifen resistance in breast cancer cells.","method":"ChIP at DLEU2 promoter, reporter assays, ectopic E2F7 expression, miRNA quantification, cell viability assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating competitive binding plus functional downstream consequence, single lab","pmids":["26397135"],"is_preprint":false},{"year":2020,"finding":"E2F7 promotes transcription of EZH2 by binding to its promoter, increasing H3K27me3 levels. EZH2 then recruits H3K27me3 to the PTEN promoter, suppressing PTEN expression and activating the AKT/mTOR signaling pathway in glioblastoma.","method":"ChIP, luciferase reporter assay, siRNA/shRNA knockdown, western blot, in vivo xenograft","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP and luciferase validating E2F7 at EZH2 promoter, functional pathway established, single lab","pmids":["32814835"],"is_preprint":false},{"year":2022,"finding":"VIRMA mediates m6A methylation of the E2F7 3'-UTR; IGF2BP2 then binds and stabilizes E2F7 mRNA. In NPC, E2F7 functions as an oncogenic transcriptional activator (rather than repressor) and cooperates with CBFB-recruited RUNX1 to transactivate ITGA2, ITGA5, and NTRK1, strengthening Akt signaling.","method":"m6A-seq/MeRIP, RIP, integrative high-throughput sequencing (ChIP-seq/RNA-seq), Co-IP, in vitro and in vivo functional assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal sequencing and biochemical methods, but single lab and novel non-canonical mechanism requires replication","pmids":["37028765"],"is_preprint":false},{"year":2022,"finding":"SAPCD2 directly binds cytoplasmic E2F7 (but not E2F1), alters E2F7 subcellular distribution, and reduces nuclear E2F7. SAPCD2 knockdown increases nuclear E2F7, affecting expression of cell cycle and chromosome instability genes. The XPO1 inhibitor selinexor induces nuclear accumulation of E2F7 and suppresses neuroblastoma growth.","method":"Co-IP (SAPCD2-E2F7 interaction), subcellular fractionation, gene expression analysis, selinexor treatment, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding shown by Co-IP with functional localization consequence, consistent with XPO1-dependent export mechanism from PMID:29950445","pmids":["35197448"],"is_preprint":false},{"year":2022,"finding":"E2F7 directly suppresses TSC1 gene transcription by binding to its promoter, thereby suppressing mTOR complex 1 and stabilizing HIF-1α, whose downstream gene activation drives mTOR inhibitor resistance in hepatocellular carcinoma under hypoxia.","method":"ChIP at TSC1 promoter, reporter assays, western blot, HIF-1α stability assays, in vivo xenograft with sirolimus","journal":"American journal of transplantation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP-based direct binding established with functional downstream pathway, single lab study","pmids":["35729702"],"is_preprint":false},{"year":2023,"finding":"E2F7 drives autotaxin (ENPP2) transcription through cooperative binding to two E2F7 sites (promoter -1393 bp and second intron 996 bp). Chromosome conformation capture showed that chromosomal looping brings these two sites together. p53 binding to the first intron of murine Enpp2 disrupts E2F7-mediated looping and represses transcription, but this mechanism does not operate in human carcinoma cells.","method":"ChIP, yeast one-hybrid, chromosome immunoprecipitation, chromosome conformation capture (3C), reporter assays, shRNA knockdown","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — 3C demonstrating chromosomal looping plus ChIP and reporter assays, single lab with orthogonal methods","pmids":["37358838"],"is_preprint":false},{"year":2025,"finding":"PRMT1-mediated arginine methylation of E2F7 maintains E2F7 protein stability (preventing its ubiquitination/degradation). E2F7 in turn transcriptionally activates SIRT6 by binding its promoter. This PRMT1→E2F7→SIRT6 axis inhibits vascular smooth muscle cell senescence in aortic dissection.","method":"Co-IP, GST pull-down, ChIP, luciferase reporter, ubiquitination assay, senescence-associated β-galactosidase staining","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods establishing PTM and downstream transcriptional mechanism, single lab","pmids":["40298071"],"is_preprint":false},{"year":2021,"finding":"E2F7 directly binds the promoter of KPNA2 (karyopherin alpha 2) competing against DP1 and blocking E2F1-induced KPNA2 activation. Mutation of E2F7 dimerization residues or E2F1 DNA-binding domain abolishes the suppressive effect. KPNA2 in turn mediates nuclear localization of both E2F1 and E2F7.","method":"ChIP, reporter assays, mutagenesis of dimerization residues/DBD, Co-IP, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus mutagenesis establishing mechanistic competition, single lab with multiple orthogonal approaches","pmids":["30254209"],"is_preprint":false},{"year":2024,"finding":"E2F7 transcriptionally represses MYBL2 (in contrast to E2F1 which activates it) in gastric cancer cells, demonstrated by ChIP and luciferase reporter assays. The opposing effects of E2F1 and E2F7 on MYBL2 regulate GC cell proliferation through the PI3K/AKT signaling pathway. Differential nucleocytoplasmic distribution of E2F7 in GC cells has functional relevance.","method":"ChIP, dual-luciferase reporter assay, siRNA knockdown, in vitro and ex vivo proliferation assays, fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and functional rescue established by orthogonal methods, single lab","pmids":["39613162"],"is_preprint":false},{"year":2025,"finding":"HuR RNA-binding protein upregulates E2F7 expression by increasing the stability of E2F7 mRNA in multiple myeloma cells. E2F7 knockdown has anti-MM effects in vitro and in vivo; E2F7 overexpression partially rescues cell proliferation inhibition caused by HuR targeting.","method":"RNA-seq, RIP (HuR-E2F7 mRNA interaction), shRNA knockdown, ectopic expression, in vivo xenograft","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RIP demonstrating direct mRNA-protein interaction plus functional rescue, single lab, novel mechanism","pmids":["40133626"],"is_preprint":false},{"year":2016,"finding":"Keratinocyte-specific loss of E2F7 and E2F8 results in increased expression of E2F1 upon stress (DNA damage, high confluence), triggering apoptosis. In DMBA/TPA skin carcinogenesis, combined inactivation of E2f7/8 enhances tumorigenesis. Additional loss of E2f1 worsens (not rescues) skin tumorigenesis, indicating that the tumor-promoting effect of E2F7/8 loss is only partially compensated by E2F1-dependent apoptosis.","method":"Conditional knockout (keratinocyte-specific), DMBA/TPA carcinogenesis protocol, genetic epistasis (E2f1 deletion), gene expression analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with clear epistasis and multiple experimental conditions","pmids":["27452520"],"is_preprint":false}],"current_model":"E2F7 is an atypical transcriptional repressor with two DNA-binding domains that binds E2F consensus sites independently of DP co-factors, repressing a specific subset of E2F target genes (including E2F1, DHFR, RAD51, VEGFA, p21, and others) by recruiting co-repressors CtBP and HDAC; it is cell-cycle-regulated (peaking in S phase), targeted for degradation by APC/C-Cdh1 in G1 and SCF-Cyclin F in G2, subject to XPO1-dependent nuclear export that can inactivate it in cancer, post-translationally stabilized by PRMT1-mediated arginine methylation, and acts downstream of p53 to couple the DNA damage response with transcriptional repression of cell cycle and DNA repair genes while also forming activating complexes (with HIF1) to promote VEGFA transcription and angiogenesis."},"narrative":{"mechanistic_narrative":"E2F7 is an atypical, DP-independent E2F transcription factor that uses two tandem DNA-binding domains to occupy E2F consensus sites and repress a defined subset of E2F target genes, thereby enforcing cell-cycle arrest and coupling proliferation control to genome maintenance [PMID:14633988, PMID:12893818, PMID:15133492, PMID:22180533]. It binds DNA most likely as a homodimer in which the two DBDs mimic an E2F/DP heterodimer, and it can also heterodimerize with E2F8 and E2F1 to compete for and silence shared promoters such as E2F1 itself [PMID:15133492, PMID:18194653, PMID:23853115]. Repression is executed by recruiting the co-repressor CtBP through a canonical PIDLS motif together with HDAC activity, remodeling chromatin both at promoters and at sites of DNA damage [PMID:23853115, PMID:23974101, PMID:24955216]. E2F7 is a transcriptional effector of p53: upon genotoxic stress and during oncogene-induced senescence, p53 directly induces E2F7, which then represses E2F1, DHFR, RAD51 and other replication and repair genes to halt the cell cycle and restrict homologous recombination [PMID:22802528, PMID:22802529, PMID:30032296, PMID:29590434]. Its protein level is tightly cell-cycle-gated, with degradation imposed in G2 by SCF–Cyclin F via a C-terminal CY degron and stability conferred by PRMT1-mediated arginine methylation [PMID:31475738, PMID:40298071], while its activity is governed by nucleocytoplasmic partitioning, where XPO1-dependent export and the cytoplasmic anchor SAPCD2 inactivate E2F7 to derepress oncogenic targets in cancer [PMID:29950445, PMID:35197448]. Beyond repression, E2F7 forms an activating complex with HIF1 to stimulate VEGFA and govern vascular and neuronal patterning genes such as NRP1, demonstrating a context-dependent dual transcriptional output [PMID:22903062, PMID:26681691].","teleology":[{"year":2003,"claim":"Established that E2F7 is a non-canonical E2F that binds E2F sites without a DP partner and represses, rather than activates, target genes—defining a distinct repressive arm of the E2F family.","evidence":"Ectopic expression, ChIP, reporter assays, nuclear fractionation and proliferation assays in MEFs","pmids":["14633988","12893818"],"confidence":"High","gaps":["DNA-binding stoichiometry not yet resolved","co-repressor machinery not identified","subset of targets not defined genome-wide"]},{"year":2004,"claim":"Resolved the mechanistic basis of DP-independent binding by showing both DBDs are required and E2F7 likely binds as a homodimer mimicking an E2F/DP heterodimer.","evidence":"Mutational analysis of both DBDs, DNA-binding assays and protein modeling","pmids":["15133492"],"confidence":"High","gaps":["no crystal structure of the DNA-bound homodimer","heterodimer partners not yet defined"]},{"year":2008,"claim":"Placed E2F7 (with E2F8) genetically upstream of E2F1 in an apoptotic and DNA-damage axis, showing it restrains E2F1/p53 to control survival and proliferation in vivo.","evidence":"Conditional knockout mice, ChIP, genetic epistasis with E2f1/p53, and DNA-damage knockdown in cells","pmids":["18194653","18202719"],"confidence":"High","gaps":["repression mechanism at E2F1 promoter not yet molecularly defined","redundancy split between E2F7 and E2F8 unresolved"]},{"year":2011,"claim":"Defined the genome-wide direct target set and cell-cycle timing, showing S-phase-peaking E2F7 represses replication, metabolism and repair genes and triggers S-phase arrest with DNA damage when mistimed.","evidence":"ChIP-seq, inducible overexpression, microarray, flow cytometry and comet assay","pmids":["22180533"],"confidence":"High","gaps":["mechanism of cell-cycle-phase-specific activity not explained","co-factors at target promoters not identified"]},{"year":2012,"claim":"Identified E2F7 as a direct p53 target that enforces DNA-damage and senescence arrest and cooperates with/compensates for RB, integrating it into tumor-suppressive checkpoint circuitry.","evidence":"ChIP for p53 at E2F7 promoter and E2F7 at targets, knockdown, oncogene-induced senescence models and RB-loss epistasis","pmids":["22802528","22802529"],"confidence":"High","gaps":["how p53 selects E2F7 among E2F genes unclear","kinetics relative to RB pathway not dissected"]},{"year":2012,"claim":"Revealed a non-repressive role: E2F7/8 partner with HIF1 to activate VEGFA and drive angiogenesis, establishing dual transcriptional output.","evidence":"Reporter assays, ChIP and vascular knockout phenotypes in zebrafish and mice","pmids":["22903062"],"confidence":"High","gaps":["molecular contacts between E2F7 and HIF1 not mapped","determinants of activation vs repression unknown"]},{"year":2013,"claim":"Identified CtBP as the obligate co-repressor and extended E2F7 function to a transcription-independent role in DNA repair through chromatin remodeling at lesions.","evidence":"In vitro DNA-binding and Co-IP, CtBP2 knockdown, laser micro-irradiation and HDAC/CtBP recruitment at damage sites","pmids":["23853115","23974101"],"confidence":"High","gaps":["transcription-independent repair role rests on single-lab abstract-level data","HDAC isoform identity not specified"]},{"year":2014,"claim":"Mapped the CtBP interaction to a canonical PIDLS motif and confirmed CtBP-dependence of repression and DNA-damage function biochemically.","evidence":"MS interactome of CtBP2, Co-IP, PIDLS mutagenesis and functional reporter/proliferation assays","pmids":["24955216"],"confidence":"Medium","gaps":["single-lab interactome","relative contribution of CtBP1 vs CtBP2 not quantified"]},{"year":2015,"claim":"Extended the HIF1–E2F7 complex to genome-wide co-regulation including repression of NRP1 controlling neuronal axon guidance, showing developmental reach beyond the cell cycle.","evidence":"ChIP-seq, RNA-seq, reporter assays and in vivo zebrafish knockdown/TALEN editing","pmids":["26681691"],"confidence":"High","gaps":["switch between stimulatory and repressive outputs at HIF1-shared loci not explained"]},{"year":2016,"claim":"Showed E2F7 shapes the miRNA landscape, repressing proliferative miRNAs and indirectly tuning let-7 maturation via an E2F/c-MYC/LIN28B axis.","evidence":"Genome-wide RNA-seq, ChIP, reporter and knockdown assays","pmids":["26961310"],"confidence":"High","gaps":["direct vs indirect contributions to let-7 not fully separated"]},{"year":2018,"claim":"Demonstrated that nucleocytoplasmic control of E2F7 is a clinically actionable switch: XPO1-dependent export mislocalizes E2F7 in cancer, derepressing oncogenic targets, reversible by selinexor.","evidence":"XPO1 inhibition, fractionation, tumor IHC, SPHK1 ChIP and xenografts in HNSCC","pmids":["29950445"],"confidence":"High","gaps":["signals triggering export not defined","generality across tumor types unestablished at the time"]},{"year":2018,"claim":"Established E2F7 as a restrictor of homologous recombination via RAD51 repression, modulating chemosensitivity of BRCA2-deficient cells and ICL responses.","evidence":"Knockdown, RAD51 ChIP, HR and replication-fork assays, 53BP1/FANCD2 foci, clonogenic survival","pmids":["30032296","29590434"],"confidence":"High","gaps":["how E2F7 selects repair genes during the cell cycle vs stress not resolved"]},{"year":2018,"claim":"Uncovered a nucleolar function: perinucleolar E2F7 represses RNA Pol I rRNA transcription by blocking UBF recruitment, linking it to global protein synthesis.","evidence":"Immunofluorescence localization, rRNA-promoter ChIP and Pol I/protein synthesis assays","pmids":["29760477"],"confidence":"Medium","gaps":["single-lab, unreplicated","mechanism of UBF exclusion not detailed"]},{"year":2019,"claim":"Defined the G2-phase degradation mechanism: SCF–Cyclin F binds a C-terminal CY degron to ubiquitinate E2F7, timing its removal to permit DNA-repair gene expression and G2/M progression.","evidence":"Co-IP, CY-motif mutagenesis, cyclin F depletion, ubiquitination assays and live-cell imaging","pmids":["31475738"],"confidence":"High","gaps":["integration with other reported degradation routes not reconciled in corpus","phosphorylation requirements for degron recognition not detailed"]},{"year":2021,"claim":"Showed E2F7 competes with DP1/E2F1 at the KPNA2 promoter and that KPNA2 reciprocally controls E2F7/E2F1 nuclear import, forming a feedback loop on its own localization.","evidence":"ChIP, dimerization/DBD mutagenesis, Co-IP and xenografts","pmids":["30254209"],"confidence":"Medium","gaps":["single-lab","physiological weight of the import feedback loop unquantified"]},{"year":2022,"claim":"Identified SAPCD2 as a cytoplasmic anchor that binds and sequesters E2F7, complementing the XPO1 export mechanism, with selinexor restoring nuclear E2F7 in neuroblastoma.","evidence":"Co-IP, fractionation, expression profiling, selinexor treatment and xenografts","pmids":["35197448"],"confidence":"Medium","gaps":["binding interface not mapped","selectivity for E2F7 over E2F1 mechanistically unexplained"]},{"year":2022,"claim":"Reported a non-canonical oncogenic activator role: m6A-stabilized E2F7 cooperates with RUNX1/CBFB to transactivate integrin and NTRK1 genes, indicating context-dependent reversal of E2F7 function.","evidence":"m6A-seq/MeRIP, RIP, integrative ChIP-seq/RNA-seq and Co-IP in NPC","pmids":["37028765"],"confidence":"Medium","gaps":["single-lab, non-canonical mechanism awaits replication","determinants of activator vs repressor switch undefined"]},{"year":2025,"claim":"Established PRMT1-mediated arginine methylation as a stabilizing post-translational mark that protects E2F7 from degradation and enables E2F7-driven SIRT6 activation against senescence.","evidence":"Co-IP, GST pull-down, ubiquitination assays, ChIP, reporter and SA-β-gal assays","pmids":["40298071"],"confidence":"Medium","gaps":["methylated residues not specified in corpus","interplay with SCF–Cyclin F degradation not tested"]},{"year":null,"claim":"How E2F7 switches between repressor and activator outputs, and how its post-translational state, partner choice and subcellular localization are integrated to select target genes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no structure of DNA-bound E2F7 complexes","rules governing activation vs repression at HIF1- and RUNX1-shared loci unknown","unified model linking degradation, methylation and export to target selection lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA 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Acts as a promoter of sprouting angiogenesis, possibly by acting as a transcription activator: associates with HIF1A, recognizes and binds the VEGFA promoter, which is different from canonical E2 recognition site, and activates expression of the VEGFA gene. 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E2F consensus DNA sites independently of DP co-factors, unlike canonical E2F family members. Ectopic expression of E2F7 suppresses E2F target genes and causes G1 accumulation. E2F7 associates with E2F-regulated promoters in vivo, with increased association during S phase, and represses only a subset of E2F-dependent promoters.\",\n      \"method\": \"Ectopic expression, ChIP, reporter assays, flow cytometry, sequence analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter assay, flow cytometry, knockdown), replicated in a second independent paper (PMID:12893818) the same year\",\n      \"pmids\": [\"14633988\", \"12893818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"E2F7 protein is localized to the nucleus, associates with DNA E2F recognition sites with high affinity, lacks a dimerization domain, transcriptional activation domain, and retinoblastoma-binding domain. E2F7 blocks E2F-dependent activation of a subset of E2F target genes and reduces cellular proliferation of mouse embryo fibroblasts.\",\n      \"method\": \"Nuclear fractionation/localization, DNA-binding assays, reporter assays, proliferation assays in MEFs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical assays with functional readout, replicated by PMID:14633988\",\n      \"pmids\": [\"12893818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"E2F7 has two separate DNA-binding domains both required for DNA binding, cell cycle delay, and transcriptional modulation. Mutational analysis shows that integrity of both DBDs is necessary. Biochemical and modeling data suggest E2F7 binds DNA most likely as a homodimer, with interactions between the two DBDs mimicking an E2F/DP heterodimer.\",\n      \"method\": \"Mutational analysis of DBDs, DNA-binding assays, protein modeling, cell cycle assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis combined with functional and biochemical validation in one study\",\n      \"pmids\": [\"15133492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"E2F7 and E2F8 form homo- and heterodimers that bind E2F target promoters including E2F1. Combined deletion of E2f7 and E2f8 in mice causes massive apoptosis and embryonic lethality by E11.5. Loss of E2F7/8 increases E2F1 and p53 levels; loss of either E2f1 or p53 suppresses the apoptosis in double-mutant embryos, establishing an E2F7/8→E2F1→p53 apoptotic axis.\",\n      \"method\": \"Conditional knockout mice, ChIP, genetic epistasis (triple mutants), immunoblotting\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with multiple orthogonal methods and full genetic rescue experiments\",\n      \"pmids\": [\"18194653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"E2F7 and E2F8 are induced by DNA-damaging agents and bind the promoter of E2F1 (coexisting in a DNA-binding complex) to repress E2F target genes including E2F1. Depletion of either E2F7 or E2F8 increases E2F1 expression and prevents the cell-cycle effects that occur in response to DNA damage, placing E2F7/8 upstream of E2F1 in the DNA damage response.\",\n      \"method\": \"ChIP, siRNA knockdown, reporter assays, flow cytometry after DNA damage\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal ChIP and functional knockdown with specific phenotypic readout, replicated direction consistent with PMID:18194653\",\n      \"pmids\": [\"18202719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"E2F7 is highly expressed during mid-to-late S phase, occupies promoters of G1/S-regulated genes (preferentially binding the TTCCCGCC motif), and directly represses their transcription. ChIP-seq identified 89 direct E2F7 target genes involved in DNA replication, metabolism, and DNA repair. Induction of E2F7 during G0-G1/S causes S-phase arrest and DNA damage, whereas expression during G2/M does not disturb cell cycle progression.\",\n      \"method\": \"ChIP-seq, inducible overexpression, microarray, flow cytometry, comet assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide ChIP-seq plus functional inducible expression system with multiple orthogonal readouts\",\n      \"pmids\": [\"22180533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In response to DNA damage, p53 directly occupies the E2F7 promoter and transcriptionally up-regulates E2F7. E2F7 in turn occupies the E2F1 and DHFR promoters and represses them; ablation of E2F7 abrogates p53-dependent repression of these targets. This defines a p53→E2F7→E2F1/DHFR repression pathway contributing to DNA damage-induced cell cycle arrest.\",\n      \"method\": \"ChIP, siRNA knockdown, reporter assays, qPCR, proliferation assays after genotoxic stress\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP for p53 at E2F7 promoter, ChIP for E2F7 at target promoters, functional rescue; independently replicated in PMID:22802529\",\n      \"pmids\": [\"22802528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"E2F7 is the only E2F transcription factor potently up-regulated during oncogene-induced senescence as a direct p53 transcriptional target. Once induced, E2F7 binds and represses E2F target genes and cooperates with RB to enforce cell cycle arrest. When RB is disrupted, E2F7 is further induced and compensates for loss of RB by repressing mitotic E2F target genes, creating a second checkpoint.\",\n      \"method\": \"Oncogene-induced senescence model, ChIP, shRNA knockdown, epistasis experiments (RB loss), gene expression arrays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus genetic epistasis in relevant biological context; replicated p53→E2F7 axis from PMID:22802528\",\n      \"pmids\": [\"22802529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"E2F7 and E2F8 form a transcriptional complex with HIF1 to stimulate VEGFA promoter activity independent of canonical E2F binding elements, thereby promoting angiogenesis. Simultaneous deletion of E2F7/8 in zebrafish and mice causes severe vascular defects.\",\n      \"method\": \"Reporter assays, ChIP, genetic knockout in zebrafish and mice, transgenic fluorescent vessel imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter, two organism knockout models) establishing a specific molecular mechanism\",\n      \"pmids\": [\"22903062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"E2F7 forms a heterodimer with E2F1 through interactions involving the DNA-binding domains. In vitro DNA interaction assays demonstrate both E2F1-E2F7 and E2F7-E2F7 complexes on adjacent E2F-binding sites. E2F7 recruits the co-repressor CtBP, and CtBP2 is essential for E2F7-mediated repression of E2F1 transcription.\",\n      \"method\": \"In vitro DNA-binding assays, Co-IP, reporter assays, siRNA knockdown of CtBP2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution of protein-DNA complexes plus functional co-repressor requirement validated by knockdown\",\n      \"pmids\": [\"23853115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"E2F7 makes a transcription-independent contribution to DNA repair by localizing to and binding damaged DNA, where it recruits CtBP and HDAC to alter the local chromatin environment at DNA lesions. Tumor-derived E2F7 mutant alleles encode proteins with compromised transcription and DNA repair properties.\",\n      \"method\": \"Laser micro-irradiation/live imaging at damage sites, ChIP at damaged DNA, HDAC/CtBP recruitment assays, mutant allele functional analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — novel finding from single lab with direct localization and recruitment experiments, but abstract-level detail limits full tier assignment\",\n      \"pmids\": [\"23974101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"E2F7 interacts with CtBP1 and CtBP2 through a canonical CtBP-binding motif (PIDLS). CtBP2 proteome analysis confirmed E2F7 as a CtBP2-associated protein. E2F7 represses E2F1 transcription and inhibits cell proliferation in a CtBP-dependent manner; CtBP also participates in E2F7-mediated DNA damage response.\",\n      \"method\": \"Proteomic analysis (MS) of CtBP2-associated proteins, Co-IP, reporter assays, proliferation assays, mutagenesis of PIDLS motif\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome plus functional validation, single lab\",\n      \"pmids\": [\"24955216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"E2F7 and HIF1α form a transcriptional complex that co-regulates a genome-wide network of genes with both stimulatory and repressive functions. The HIF1α-E2F7 complex represses Neuropilin 1 (NRP1) through a 41 bp E2F-binding site hub, and this repression regulates motor neuron axon guidance in vivo in zebrafish.\",\n      \"method\": \"ChIP-seq, genome-wide RNA-seq, in vitro reporter assays, in vivo zebrafish morpholino knockdown, TALEN mutagenesis, in situ hybridization\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP-seq plus genome-wide expression analysis with in vivo genetic rescue in two organisms\",\n      \"pmids\": [\"26681691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"E2F7 transcriptionally represses a set of proliferation-promoting microRNAs (miR-25, -26a, -27b, -92a, -7) by antagonizing E2F1-3 at their promoters. Additionally, E2F7 indirectly controls let-7 miRNA processing and maturation through a novel E2F/c-MYC/LIN28B axis, whereby E2F7 and E2F1-3 modulate c-MYC and LIN28B levels.\",\n      \"method\": \"Genome-wide RNA-seq, ChIP, reporter assays, siRNA knockdown, qPCR\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide approach combined with ChIP and functional validation in a single lab study\",\n      \"pmids\": [\"26961310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"E2F7 binds the p21(CIP1/WAF1) promoter and represses its expression in AML cells, promoting cell cycle progression. Interference with E2F7 expression results in inhibition of c-Myc transcriptional activity and downregulation of the miR-17-92 cluster, which contributes to monocytic differentiation block.\",\n      \"method\": \"ChIP, reporter assays, siRNA knockdown, flow cytometry, differentiation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct binding to p21 promoter plus functional pathway analysis, single lab\",\n      \"pmids\": [\"23096114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"E2F7 is subject to XPO1 (exportin 1)-dependent nuclear export and is mislocalized to the cytoplasm in >80% of head and neck squamous cell carcinomas (HNSCC). This cytoplasmic mislocalization causes derepression of the E2F7 target SPHK1, driving anthracycline resistance. Treatment with the XPO1 inhibitor selinexor restores nuclear E2F7 and reverses resistance in xenotransplant models.\",\n      \"method\": \"XPO1 inhibitor treatment, nuclear/cytoplasmic fractionation, IHC of human tumors, ChIP for SPHK1 promoter, xenograft models\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with functional consequence, mechanistic linkage to specific target gene, in vivo validation\",\n      \"pmids\": [\"29950445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"E2F7-mediated transcriptional repression of RAD51 modulates chemosensitivity of BRCA2-deficient cells. Loss of E2F7 increases RAD51 expression, enhances homologous recombination DNA repair and replication fork stability in BRCA2-deficient cells, and confers resistance to PARP inhibitors and cisplatin.\",\n      \"method\": \"siRNA/shRNA knockdown, ChIP for RAD51 promoter, HR assay, replication fork assay, cell viability assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct E2F7 occupancy at RAD51 promoter, functional HR assay, mechanistic pathway established\",\n      \"pmids\": [\"30032296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"E2F7 represses the expression of genes involved in DNA repair (including RAD51) both throughout the cell cycle and upon induction of DNA interstrand crosslink lesions. E2F7 knockdown reduces 53BP1 and FANCD2 foci, decreases chromosomal aberrations after ICL-inducing agents (but not ionizing radiation), and enhances clonogenic survival after ICL, establishing E2F7 as a restrictor of homologous recombination via RAD51 repression.\",\n      \"method\": \"siRNA knockdown, immunofluorescence (53BP1/FANCD2 foci), chromosomal aberration analysis, cell-based HR assay, clonogenic survival\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods establishing mechanism, consistent with PMID:30032296 from independent lab\",\n      \"pmids\": [\"29590434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"E2F7 localizes to the perinucleolar region and represses RNA Polymerase I (Pol I) transcription of ribosomal rRNA genes. Mechanistically, E2F7 hinders UBF (upstream binding factor) recruitment to the rRNA gene promoter, thereby reducing rRNA gene transcription and compromising global protein synthesis.\",\n      \"method\": \"Subcellular localization (immunofluorescence), ChIP at rRNA gene promoter, Pol I transcription assays, protein synthesis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization plus ChIP and functional assay from single lab, novel finding not yet replicated\",\n      \"pmids\": [\"29760477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"E2F7 is targeted for proteasomal degradation by the E3 ubiquitin ligase SCF-Cyclin F during G2 phase. Cyclin F binds via its cyclin domain to a conserved C-terminal CY motif on E2F7. An E2F7 mutant unable to interact with SCF-Cyclin F remains stable during G2. Cyclin F depletion causes atypical-E2F-dependent delay of G2/M transition and reduced expression of DNA repair E2F target genes, impairing efficient DNA repair.\",\n      \"method\": \"Co-IP, CY motif mutagenesis, cyclin F depletion, live-cell imaging, ubiquitination assays, cell cycle analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis of degron motif, biochemical interaction, functional consequence with live imaging, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"31475738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"E2F7-mediated suppression of proliferation and apoptosis in keratinocytes acts through E2F1-dependent pathways, whereas E2F7-induced differentiation acts through an E2F1-independent pathway. Inhibition of E2F7 in SCC cells sensitizes them to UV- and doxorubicin-induced apoptosis.\",\n      \"method\": \"Ectopic expression, siRNA knockdown, proliferation/apoptosis assays, differentiation marker assays in primary human keratinocytes\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis between E2F7 and E2F1 established by double-manipulation experiments with multiple phenotypic readouts\",\n      \"pmids\": [\"19223542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"E2F7 binds to a unique binding site between -139 and -119 bp of the Sp1 promoter in differentiating keratinocytes. Knockdown of E2F7 in proliferating keratinocytes leads to derepression of Sp1 expression and induction of the differentiation gene TG1. E2F4 knockdown does not alter Sp1 expression, indicating E2F7-specific regulation.\",\n      \"method\": \"ChIP, transient transfection, shRNA knockdown, reporter assays with deletion mapping\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assays with functional knockdown, single lab, clear mechanistic dissection\",\n      \"pmids\": [\"21248772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"E2F7 competes with E2F1 for binding at the E2F binding site on the miR-15a/16 host gene DLEU2 promoter. Overexpression of E2F7 represses miR-15a/16, leading to increased Cyclin E1 and Bcl-2 and conferring tamoxifen resistance in breast cancer cells.\",\n      \"method\": \"ChIP at DLEU2 promoter, reporter assays, ectopic E2F7 expression, miRNA quantification, cell viability assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating competitive binding plus functional downstream consequence, single lab\",\n      \"pmids\": [\"26397135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"E2F7 promotes transcription of EZH2 by binding to its promoter, increasing H3K27me3 levels. EZH2 then recruits H3K27me3 to the PTEN promoter, suppressing PTEN expression and activating the AKT/mTOR signaling pathway in glioblastoma.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA/shRNA knockdown, western blot, in vivo xenograft\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP and luciferase validating E2F7 at EZH2 promoter, functional pathway established, single lab\",\n      \"pmids\": [\"32814835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VIRMA mediates m6A methylation of the E2F7 3'-UTR; IGF2BP2 then binds and stabilizes E2F7 mRNA. In NPC, E2F7 functions as an oncogenic transcriptional activator (rather than repressor) and cooperates with CBFB-recruited RUNX1 to transactivate ITGA2, ITGA5, and NTRK1, strengthening Akt signaling.\",\n      \"method\": \"m6A-seq/MeRIP, RIP, integrative high-throughput sequencing (ChIP-seq/RNA-seq), Co-IP, in vitro and in vivo functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal sequencing and biochemical methods, but single lab and novel non-canonical mechanism requires replication\",\n      \"pmids\": [\"37028765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SAPCD2 directly binds cytoplasmic E2F7 (but not E2F1), alters E2F7 subcellular distribution, and reduces nuclear E2F7. SAPCD2 knockdown increases nuclear E2F7, affecting expression of cell cycle and chromosome instability genes. The XPO1 inhibitor selinexor induces nuclear accumulation of E2F7 and suppresses neuroblastoma growth.\",\n      \"method\": \"Co-IP (SAPCD2-E2F7 interaction), subcellular fractionation, gene expression analysis, selinexor treatment, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown by Co-IP with functional localization consequence, consistent with XPO1-dependent export mechanism from PMID:29950445\",\n      \"pmids\": [\"35197448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"E2F7 directly suppresses TSC1 gene transcription by binding to its promoter, thereby suppressing mTOR complex 1 and stabilizing HIF-1α, whose downstream gene activation drives mTOR inhibitor resistance in hepatocellular carcinoma under hypoxia.\",\n      \"method\": \"ChIP at TSC1 promoter, reporter assays, western blot, HIF-1α stability assays, in vivo xenograft with sirolimus\",\n      \"journal\": \"American journal of transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP-based direct binding established with functional downstream pathway, single lab study\",\n      \"pmids\": [\"35729702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"E2F7 drives autotaxin (ENPP2) transcription through cooperative binding to two E2F7 sites (promoter -1393 bp and second intron 996 bp). Chromosome conformation capture showed that chromosomal looping brings these two sites together. p53 binding to the first intron of murine Enpp2 disrupts E2F7-mediated looping and represses transcription, but this mechanism does not operate in human carcinoma cells.\",\n      \"method\": \"ChIP, yeast one-hybrid, chromosome immunoprecipitation, chromosome conformation capture (3C), reporter assays, shRNA knockdown\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — 3C demonstrating chromosomal looping plus ChIP and reporter assays, single lab with orthogonal methods\",\n      \"pmids\": [\"37358838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRMT1-mediated arginine methylation of E2F7 maintains E2F7 protein stability (preventing its ubiquitination/degradation). E2F7 in turn transcriptionally activates SIRT6 by binding its promoter. This PRMT1→E2F7→SIRT6 axis inhibits vascular smooth muscle cell senescence in aortic dissection.\",\n      \"method\": \"Co-IP, GST pull-down, ChIP, luciferase reporter, ubiquitination assay, senescence-associated β-galactosidase staining\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods establishing PTM and downstream transcriptional mechanism, single lab\",\n      \"pmids\": [\"40298071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"E2F7 directly binds the promoter of KPNA2 (karyopherin alpha 2) competing against DP1 and blocking E2F1-induced KPNA2 activation. Mutation of E2F7 dimerization residues or E2F1 DNA-binding domain abolishes the suppressive effect. KPNA2 in turn mediates nuclear localization of both E2F1 and E2F7.\",\n      \"method\": \"ChIP, reporter assays, mutagenesis of dimerization residues/DBD, Co-IP, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus mutagenesis establishing mechanistic competition, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"30254209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"E2F7 transcriptionally represses MYBL2 (in contrast to E2F1 which activates it) in gastric cancer cells, demonstrated by ChIP and luciferase reporter assays. The opposing effects of E2F1 and E2F7 on MYBL2 regulate GC cell proliferation through the PI3K/AKT signaling pathway. Differential nucleocytoplasmic distribution of E2F7 in GC cells has functional relevance.\",\n      \"method\": \"ChIP, dual-luciferase reporter assay, siRNA knockdown, in vitro and ex vivo proliferation assays, fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and functional rescue established by orthogonal methods, single lab\",\n      \"pmids\": [\"39613162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HuR RNA-binding protein upregulates E2F7 expression by increasing the stability of E2F7 mRNA in multiple myeloma cells. E2F7 knockdown has anti-MM effects in vitro and in vivo; E2F7 overexpression partially rescues cell proliferation inhibition caused by HuR targeting.\",\n      \"method\": \"RNA-seq, RIP (HuR-E2F7 mRNA interaction), shRNA knockdown, ectopic expression, in vivo xenograft\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RIP demonstrating direct mRNA-protein interaction plus functional rescue, single lab, novel mechanism\",\n      \"pmids\": [\"40133626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Keratinocyte-specific loss of E2F7 and E2F8 results in increased expression of E2F1 upon stress (DNA damage, high confluence), triggering apoptosis. In DMBA/TPA skin carcinogenesis, combined inactivation of E2f7/8 enhances tumorigenesis. Additional loss of E2f1 worsens (not rescues) skin tumorigenesis, indicating that the tumor-promoting effect of E2F7/8 loss is only partially compensated by E2F1-dependent apoptosis.\",\n      \"method\": \"Conditional knockout (keratinocyte-specific), DMBA/TPA carcinogenesis protocol, genetic epistasis (E2f1 deletion), gene expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with clear epistasis and multiple experimental conditions\",\n      \"pmids\": [\"27452520\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"E2F7 is an atypical transcriptional repressor with two DNA-binding domains that binds E2F consensus sites independently of DP co-factors, repressing a specific subset of E2F target genes (including E2F1, DHFR, RAD51, VEGFA, p21, and others) by recruiting co-repressors CtBP and HDAC; it is cell-cycle-regulated (peaking in S phase), targeted for degradation by APC/C-Cdh1 in G1 and SCF-Cyclin F in G2, subject to XPO1-dependent nuclear export that can inactivate it in cancer, post-translationally stabilized by PRMT1-mediated arginine methylation, and acts downstream of p53 to couple the DNA damage response with transcriptional repression of cell cycle and DNA repair genes while also forming activating complexes (with HIF1) to promote VEGFA transcription and angiogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"E2F7 is an atypical, DP-independent E2F transcription factor that uses two tandem DNA-binding domains to occupy E2F consensus sites and repress a defined subset of E2F target genes, thereby enforcing cell-cycle arrest and coupling proliferation control to genome maintenance [#0, #2, #5]. It binds DNA most likely as a homodimer in which the two DBDs mimic an E2F/DP heterodimer, and it can also heterodimerize with E2F8 and E2F1 to compete for and silence shared promoters such as E2F1 itself [#2, #3, #9]. Repression is executed by recruiting the co-repressor CtBP through a canonical PIDLS motif together with HDAC activity, remodeling chromatin both at promoters and at sites of DNA damage [#9, #10, #11]. E2F7 is a transcriptional effector of p53: upon genotoxic stress and during oncogene-induced senescence, p53 directly induces E2F7, which then represses E2F1, DHFR, RAD51 and other replication and repair genes to halt the cell cycle and restrict homologous recombination [#6, #7, #16, #17]. Its protein level is tightly cell-cycle-gated, with degradation imposed in G2 by SCF–Cyclin F via a C-terminal CY degron and stability conferred by PRMT1-mediated arginine methylation [#19, #28], while its activity is governed by nucleocytoplasmic partitioning, where XPO1-dependent export and the cytoplasmic anchor SAPCD2 inactivate E2F7 to derepress oncogenic targets in cancer [#15, #25]. Beyond repression, E2F7 forms an activating complex with HIF1 to stimulate VEGFA and govern vascular and neuronal patterning genes such as NRP1, demonstrating a context-dependent dual transcriptional output [#8, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that E2F7 is a non-canonical E2F that binds E2F sites without a DP partner and represses, rather than activates, target genes—defining a distinct repressive arm of the E2F family.\",\n      \"evidence\": \"Ectopic expression, ChIP, reporter assays, nuclear fractionation and proliferation assays in MEFs\",\n      \"pmids\": [\"14633988\", \"12893818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DNA-binding stoichiometry not yet resolved\", \"co-repressor machinery not identified\", \"subset of targets not defined genome-wide\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the mechanistic basis of DP-independent binding by showing both DBDs are required and E2F7 likely binds as a homodimer mimicking an E2F/DP heterodimer.\",\n      \"evidence\": \"Mutational analysis of both DBDs, DNA-binding assays and protein modeling\",\n      \"pmids\": [\"15133492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no crystal structure of the DNA-bound homodimer\", \"heterodimer partners not yet defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed E2F7 (with E2F8) genetically upstream of E2F1 in an apoptotic and DNA-damage axis, showing it restrains E2F1/p53 to control survival and proliferation in vivo.\",\n      \"evidence\": \"Conditional knockout mice, ChIP, genetic epistasis with E2f1/p53, and DNA-damage knockdown in cells\",\n      \"pmids\": [\"18194653\", \"18202719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"repression mechanism at E2F1 promoter not yet molecularly defined\", \"redundancy split between E2F7 and E2F8 unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the genome-wide direct target set and cell-cycle timing, showing S-phase-peaking E2F7 represses replication, metabolism and repair genes and triggers S-phase arrest with DNA damage when mistimed.\",\n      \"evidence\": \"ChIP-seq, inducible overexpression, microarray, flow cytometry and comet assay\",\n      \"pmids\": [\"22180533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism of cell-cycle-phase-specific activity not explained\", \"co-factors at target promoters not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified E2F7 as a direct p53 target that enforces DNA-damage and senescence arrest and cooperates with/compensates for RB, integrating it into tumor-suppressive checkpoint circuitry.\",\n      \"evidence\": \"ChIP for p53 at E2F7 promoter and E2F7 at targets, knockdown, oncogene-induced senescence models and RB-loss epistasis\",\n      \"pmids\": [\"22802528\", \"22802529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how p53 selects E2F7 among E2F genes unclear\", \"kinetics relative to RB pathway not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a non-repressive role: E2F7/8 partner with HIF1 to activate VEGFA and drive angiogenesis, establishing dual transcriptional output.\",\n      \"evidence\": \"Reporter assays, ChIP and vascular knockout phenotypes in zebrafish and mice\",\n      \"pmids\": [\"22903062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular contacts between E2F7 and HIF1 not mapped\", \"determinants of activation vs repression unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified CtBP as the obligate co-repressor and extended E2F7 function to a transcription-independent role in DNA repair through chromatin remodeling at lesions.\",\n      \"evidence\": \"In vitro DNA-binding and Co-IP, CtBP2 knockdown, laser micro-irradiation and HDAC/CtBP recruitment at damage sites\",\n      \"pmids\": [\"23853115\", \"23974101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"transcription-independent repair role rests on single-lab abstract-level data\", \"HDAC isoform identity not specified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped the CtBP interaction to a canonical PIDLS motif and confirmed CtBP-dependence of repression and DNA-damage function biochemically.\",\n      \"evidence\": \"MS interactome of CtBP2, Co-IP, PIDLS mutagenesis and functional reporter/proliferation assays\",\n      \"pmids\": [\"24955216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single-lab interactome\", \"relative contribution of CtBP1 vs CtBP2 not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the HIF1–E2F7 complex to genome-wide co-regulation including repression of NRP1 controlling neuronal axon guidance, showing developmental reach beyond the cell cycle.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, reporter assays and in vivo zebrafish knockdown/TALEN editing\",\n      \"pmids\": [\"26681691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"switch between stimulatory and repressive outputs at HIF1-shared loci not explained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed E2F7 shapes the miRNA landscape, repressing proliferative miRNAs and indirectly tuning let-7 maturation via an E2F/c-MYC/LIN28B axis.\",\n      \"evidence\": \"Genome-wide RNA-seq, ChIP, reporter and knockdown assays\",\n      \"pmids\": [\"26961310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct vs indirect contributions to let-7 not fully separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that nucleocytoplasmic control of E2F7 is a clinically actionable switch: XPO1-dependent export mislocalizes E2F7 in cancer, derepressing oncogenic targets, reversible by selinexor.\",\n      \"evidence\": \"XPO1 inhibition, fractionation, tumor IHC, SPHK1 ChIP and xenografts in HNSCC\",\n      \"pmids\": [\"29950445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"signals triggering export not defined\", \"generality across tumor types unestablished at the time\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established E2F7 as a restrictor of homologous recombination via RAD51 repression, modulating chemosensitivity of BRCA2-deficient cells and ICL responses.\",\n      \"evidence\": \"Knockdown, RAD51 ChIP, HR and replication-fork assays, 53BP1/FANCD2 foci, clonogenic survival\",\n      \"pmids\": [\"30032296\", \"29590434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how E2F7 selects repair genes during the cell cycle vs stress not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered a nucleolar function: perinucleolar E2F7 represses RNA Pol I rRNA transcription by blocking UBF recruitment, linking it to global protein synthesis.\",\n      \"evidence\": \"Immunofluorescence localization, rRNA-promoter ChIP and Pol I/protein synthesis assays\",\n      \"pmids\": [\"29760477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single-lab, unreplicated\", \"mechanism of UBF exclusion not detailed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the G2-phase degradation mechanism: SCF–Cyclin F binds a C-terminal CY degron to ubiquitinate E2F7, timing its removal to permit DNA-repair gene expression and G2/M progression.\",\n      \"evidence\": \"Co-IP, CY-motif mutagenesis, cyclin F depletion, ubiquitination assays and live-cell imaging\",\n      \"pmids\": [\"31475738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"integration with other reported degradation routes not reconciled in corpus\", \"phosphorylation requirements for degron recognition not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed E2F7 competes with DP1/E2F1 at the KPNA2 promoter and that KPNA2 reciprocally controls E2F7/E2F1 nuclear import, forming a feedback loop on its own localization.\",\n      \"evidence\": \"ChIP, dimerization/DBD mutagenesis, Co-IP and xenografts\",\n      \"pmids\": [\"30254209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single-lab\", \"physiological weight of the import feedback loop unquantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified SAPCD2 as a cytoplasmic anchor that binds and sequesters E2F7, complementing the XPO1 export mechanism, with selinexor restoring nuclear E2F7 in neuroblastoma.\",\n      \"evidence\": \"Co-IP, fractionation, expression profiling, selinexor treatment and xenografts\",\n      \"pmids\": [\"35197448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"binding interface not mapped\", \"selectivity for E2F7 over E2F1 mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported a non-canonical oncogenic activator role: m6A-stabilized E2F7 cooperates with RUNX1/CBFB to transactivate integrin and NTRK1 genes, indicating context-dependent reversal of E2F7 function.\",\n      \"evidence\": \"m6A-seq/MeRIP, RIP, integrative ChIP-seq/RNA-seq and Co-IP in NPC\",\n      \"pmids\": [\"37028765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single-lab, non-canonical mechanism awaits replication\", \"determinants of activator vs repressor switch undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established PRMT1-mediated arginine methylation as a stabilizing post-translational mark that protects E2F7 from degradation and enables E2F7-driven SIRT6 activation against senescence.\",\n      \"evidence\": \"Co-IP, GST pull-down, ubiquitination assays, ChIP, reporter and SA-β-gal assays\",\n      \"pmids\": [\"40298071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"methylated residues not specified in corpus\", \"interplay with SCF–Cyclin F degradation not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How E2F7 switches between repressor and activator outputs, and how its post-translational state, partner choice and subcellular localization are integrated to select target genes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no structure of DNA-bound E2F7 complexes\", \"rules governing activation vs repression at HIF1- and RUNX1-shared loci unknown\", \"unified model linking degradation, methylation and export to target selection lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 5, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 6, 8, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 15]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 5, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 6, 9, 13]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\n      \"E2F7-E2F8 dimer\",\n      \"HIF1-E2F7 transcriptional complex\"\n    ],\n    \"partners\": [\n      \"E2F8\",\n      \"E2F1\",\n      \"CtBP1\",\n      \"CtBP2\",\n      \"HIF1A\",\n      \"CCNF\",\n      \"PRMT1\",\n      \"SAPCD2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}