Affinage

KMT5A

N-lysine methyltransferase KMT5A · UniProt Q9NQR1

Length
393 aa
Mass
42.9 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KMT5A (SET8/PR-Set7/SETD8) is the sole mammalian enzyme that monomethylates histone H4 at lysine 20 (H4K20me1), a single-subunit methyltransferase that prefers nucleosomal substrate and whose loss is lethal in Drosophila and mice (PMID:12121615, PMID:12086618, PMID:18166648). Crystallographic, NMR, peptide-array, kinetic-isotope, and QM/MM studies define a long, sequence-specific recognition motif around H4K20 (RHRK20VLRDN) and an SN2 catalytic mechanism that requires prior lysine deprotonation through a water channel; the methyl group installed on the product blocks channel reformation, enforcing strict monomethylation (PMID:15933070, PMID:15933069, PMID:15964846, PMID:22583696, PMID:27940912, PMID:18512960). SET8 docks onto the nucleosome through multivalent i-SET/c-SET contacts with DNA and an arginine-anchor interaction with the H2A/H2B acidic patch, and PCNA competes with the nucleosome for the same N-terminal extension, coupling its enzymatic engagement to the replication context (PMID:26953260). Beyond histones, SET8 monomethylates a panel of non-histone substrates with defined functional consequences: p53 at K382 to dampen p53 transcriptional and apoptotic output through the L3MBTL1 reader (PMID:17707234, PMID:20870725, PMID:28073004), PCNA at K248 to promote FEN1 binding and Okazaki fragment maturation (PMID:22556262), UHRF1 at K385 to trigger its degradation and limit DNMT1-dependent DNA methylation (PMID:31400111), Numb to release p53 for degradation (PMID:23706821), SNIP1 at K301 (PMID:35449131), and α-tubulin at K311 (PMID:32111740). H4K20me1 deposited by SET8 licenses replication origins via downstream Suv4-20h-mediated H4K20me3 and ORC recruitment, drives mitotic chromatin compaction, supports 53BP1 recruitment and NHEJ-mediated double-strand break repair, and enforces transcriptional repression through readers including L3MBTL1 (PMID:20953199, PMID:23152447, PMID:18480059, PMID:25252681, PMID:18474616); accordingly SET8 loss causes S-phase accumulation, re-replication, chromosome condensation failure, DNA damage, and embryonic lethality (PMID:18166648, PMID:18480059, PMID:20953199). SET8 protein abundance is gated through the cell cycle by multiple ubiquitin E3 ligases—CRL4(Cdt2) acting through a PCNA-binding PIP degron during S phase and after damage, SCF(β-TRCP) after UV damage, and APC(Cdh1) in late mitosis—counterbalanced by the deubiquitinase USP17, while CDK1/cyclinB phosphorylation at Ser29 removes it from mitotic chromosomes and shields it from APC until Cdc14 dephosphorylation (PMID:21035370, PMID:20932472, PMID:21220508, PMID:26666832, PMID:20966048, PMID:31533987).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 High

    Established the identity and core activity of the enzyme: it answered which protein deposits H4K20 methylation and whether it is essential.

    Evidence Biochemical purification, in vitro methyltransferase assay, and Drosophila genetic knockout, plus an in vitro competition assay showing H4K20 methylation and H4K16 acetylation are mutually antagonistic

    PMID:12086618 PMID:12121615

    Open questions at the time
    • Catalytic mechanism and structural basis of specificity not yet defined
    • Non-histone substrates unknown at this stage
  2. 2005 High

    Defined the structural and sequence basis for substrate recognition and why the enzyme is a strict monomethylase, answering how specificity is achieved.

    Evidence X-ray crystallography of SET8–H4 peptide–SAH complexes, NMR, deletion mapping (residues 195–352), and alanine-scanning of the RHRK20VLRDN motif

    PMID:15933069 PMID:15933070 PMID:15964846

    Open questions at the time
    • Nucleosome-level engagement not resolved by peptide structures
    • Catalytic transition-state geometry not yet measured
  3. 2007 High

    Extended the enzyme from a histone writer to a regulator of p53 and DNA replication, answering whether it has non-histone substrates and a replication role.

    Evidence In vitro methylation identifying p53 K382, RNAi/reporter assays, PCNA Co-IP via a PIP motif, DNA fiber assays, and mouse knockout

    PMID:17707234 PMID:18166648

    Open questions at the time
    • Mechanism coupling H4K20me1 to replication licensing not yet defined
    • Whether replication phenotype is p53-independent unresolved
  4. 2008 High

    Separated the enzyme's catalytic from scaffolding functions and tied catalysis to mitosis and a trans-tail code, while defining how PCNA couples methylation to S phase.

    Evidence Dominant-negative catalytic mutant cell-cycle analysis, PIP-box mutant PCNA tethering, ChIP/reporter assays for the H4K20me1–L3MBTL1–H3K9me1 axis, and QM/MM mechanism modeling

    PMID:18319261 PMID:18474616 PMID:18480059 PMID:18512960

    Open questions at the time
    • Identity of the recruited H3K9 monomethyltransferase not established here
    • QM/MM mechanism is computationally derived
  5. 2010 High

    Resolved how the enzyme is degraded and how its product feeds origin licensing and chromatin compaction, answering how its activity is temporally restricted.

    Evidence Ubiquitylation assays and degron/phospho-mutant stability analyses (CRL4(Cdt2), Skp2, APC(Cdh1), CDK1-S29), laser microirradiation for damage recruitment, tethering/ChIP for origin licensing, and crystallography of L3MBTL1 reading p53K382me1

    PMID:20870725 PMID:20932472 PMID:20953199 PMID:20966048 PMID:21035370 PMID:21220508

    Open questions at the time
    • Quantitative contribution of each E3 ligase across cell-cycle states not delineated
    • Reader landscape for H4K20me1 beyond L3MBTL1 incomplete
  6. 2012 High

    Connected H4K20me1 to the downstream H4K20me3/ORC origin pathway and added PCNA K248 methylation, refining how the enzyme supports replication fidelity.

    Evidence Conditional mouse knockout epistasis with Suv4-20h, tethering/ChIP for ORC recruitment, peptide-array motif mapping, and in vitro PCNA K248 methylation with Okazaki fragment assays

    PMID:22556262 PMID:22583696 PMID:23152447

    Open questions at the time
    • Direct ORC1/ORCA binding to H4K20me3 inferred rather than reconstituted here
    • Generality of K248 methylation across replication contexts unclear
  7. 2014 Medium

    Defined direct action at double-strand breaks and additional non-histone substrates/partners, answering how the enzyme participates in repair and apoptosis control.

    Evidence Enzymatic activity measurement at laser-induced DSBs with NHEJ reporter, Numb methylation Co-IP/apoptosis assays, and Riz1/PRDM2 pulldown/localization studies

    PMID:23706821 PMID:24423864 PMID:25252681

    Open questions at the time
    • DSB role from a single lab without reciprocal validation
    • Numb and Riz1 interactions not reconstituted structurally
  8. 2019 Medium

    Identified UHRF1 K385 methylation linking SET8 to global DNA methylation and the first stabilizing deubiquitinase, expanding the regulatory and substrate network.

    Evidence In vitro UHRF1 methylation with site mutant and bisulfite sequencing; USP17 Co-IP and in vitro deubiquitination with senescence assays

    PMID:31400111 PMID:31533987

    Open questions at the time
    • USP17 evidence from a single study
    • In vivo significance of UHRF1 methylation for genomic methylation patterns incompletely mapped
  9. 2023 Medium

    Placed H4K20 methylation in developmental ERV silencing, answering one mechanism for the embryonic lethality of SET8 loss.

    Evidence Conditional mouse knockout in trophoblasts with RNA-seq, ChIP, interferon and necroptosis assays

    PMID:37307441

    Open questions at the time
    • Single-study mechanism
    • Direct H4K20 methylation at specific ERV loci versus indirect effects not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse non-histone substrate methylations and tissue-specific transcriptional roles are coordinated with cell-cycle-gated SET8 abundance to produce context-specific outcomes remains unresolved.
  • No unified model integrating histone vs non-histone substrate choice
  • Tissue-specific corepressor partnerships (GATA-1, STAT3, TWIST) lack shared mechanistic framework
  • Substrate selection determinants in vivo undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 9 GO:0140096 catalytic activity, acting on a protein 6 GO:0140110 transcription regulator activity 4 GO:0042393 histone binding 3
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 3
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-69306 DNA Replication 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 3 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
L3MBTL1PCNAPRDM2SNIP1STAT3TP53TWIST1UHRF1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 PR-Set7/SET8 (KMT5A) was purified and identified as the enzyme responsible for monomethylation of histone H4 at lysine 20 (H4K20me1). It is a single-subunit enzyme that prefers nucleosomal substrates. Disruption of SET8 in Drosophila reduces H4K20 methylation in vivo and results in lethality. Biochemical purification, in vitro methyltransferase assay, Drosophila genetic knockout Current biology : CB High 12086618 12121615
2002 H4 lysine 20 methylation and H4 lysine 16 acetylation are mutually antagonistic modifications: in vitro, methylation of K20 and acetylation of K16 on the H4 tail are competitive. The Drosophila male X chromosome, hyperacetylated at H4K16, shows significantly decreased H4K20 methylation. In vitro competition methylation/acetylation assay, polytene chromosome immunostaining Molecular cell High 12086618
2005 Crystal structure of human SET8 bound to a histone H4 peptide bearing Lys-20 and the product cofactor S-adenosylhomocysteine revealed the structural basis of substrate specificity. Residues preceding K20 engage in salt bridge, hydrogen bond, and van der Waals interactions; C-terminal residues bind through hydrophobic interactions. Mutational analysis confirmed that interactions with N- and C-terminal H4 residues are critical for substrate specificity. SET8 functions as a monomethylase. X-ray crystallography, site-directed mutagenesis, in vitro methyltransferase assay Genes & development High 15933069 15933070
2005 NMR studies showed C-flanking domains of SET proteins become ordered upon addition of AdoMet cofactor. A histidine residue within the H4 substrate, close to target K20, is required for completion of the active site, explaining nucleosome specificity. The highly variable i-SET component is responsible for many substrate interactions. X-ray crystallography, NMR spectroscopy, in vitro methyltransferase assay Genes & development High 15933069
2005 The minimal active SET domain of SET8 maps to amino acids 195-352. SET8 recognizes the specific sequence RHRK20VLRDN in the H4 N-terminus for monomethylation; individual mutation of any charged residue in this sequence abolished or greatly decreased methylation. Mass spectrometry confirmed SET8 selectively mono-methylates K20. Deletion mapping, alanine-scanning mutagenesis, in vitro methyltransferase assay, mass spectrometry The Journal of biological chemistry High 15964846
2007 SET8 specifically monomethylates the tumor suppressor p53 at lysine 382 (p53K382me1). This methylation suppresses p53-mediated transcriptional activation of highly responsive target genes. Depletion of SET8 augments proapoptotic and checkpoint activation functions of p53. In vitro methyltransferase assay, RNAi knockdown, reporter gene assay, immunoprecipitation Molecular cell High 17707234
2007 SET8 depletion leads to decreased cell proliferation, accumulation in S phase, DNA double-strand break induction, and recruitment of DNA repair proteins (RPA, Rad51, 53BP1). SET8 interacts with PCNA through a conserved PIP motif. SET8 is required for DNA replication fork progression. SET8 deletion in mice causes embryonic lethality. siRNA knockdown, co-immunoprecipitation, DNA fiber assay, mouse genetic knockout The Journal of cell biology High 18166648
2008 SET8 monomethylates H4K20 during S phase by tethering to PCNA via a PIP box motif. The SET8-PCNA interaction couples H4K20 methylation with DNA replication. Co-immunoprecipitation, PIP-box mutant analysis, cell cycle synchronization experiments The Journal of biological chemistry High 18319261
2008 PR-Set7 catalytic activity is essential for mitotic entry and genomic stability. Loss of PR-Set7 causes G2 arrest, global chromosome condensation failure, aberrant centrosome amplification, and DNA damage. A catalytically dead dominant-negative PR-Set7 mutant recapitulates these phenotypes, demonstrating the H4K20 monomethyltransferase activity is required independently of p53. RNAi knockdown, dominant-negative catalytic mutant, cell cycle analysis, immunofluorescence The Journal of biological chemistry High 18480059
2008 PR-Set7 establishes a trans-tail histone code: H3K9 monomethylation depends on PR-Set7 but independently of its catalytic activity, indicating PR-Set7 recruits an H3K9 monomethyltransferase. This code involves L3MBTL1 binding monomethylated H4K20 to repress specific genes including RUNX1, regulating megakaryopoiesis. RNAi knockdown, ChIP, reporter assay, gene expression analysis Molecular and cellular biology Medium 18474616
2010 The L3MBTL1 chromatin compaction factor preferentially recognizes p53K382me1 (generated by SET8) through its triple MBT repeats, as demonstrated biochemically and crystallographically. SET8-mediated methylation promotes L3MBTL1-p53 interaction in cells and L3MBTL1 occupancy at p53 target promoters, repressing p53 target genes in the absence of DNA damage. Biochemical binding assay, X-ray crystallography (MBT-peptide), co-immunoprecipitation, ChIP The Journal of biological chemistry High 20870725
2010 PR-Set7 is degraded during S phase and in response to DNA damage by the CRL4(Cdt2) E3 ubiquitin ligase in a PCNA-dependent manner. A specialized 'PIP degron' in PR-Set7 mediates PCNA interaction and targets PR-Set7 for proteolysis on chromatin. A PR-Set7 mutant in the PIP degron accumulates during S phase. Skp2 also promotes PR-Set7 degradation outside the chromatin context. After DNA damage, PR-Set7 is transiently recruited to laser-induced damage sites via PCNA interaction, after which 53BP1 is recruited dependent on PR-Set7 catalytic activity. Protein stability assays, ubiquitination assay, PIP degron mutant, laser microirradiation/live imaging, siRNA knockdown Molecular cell High 20932472 21035370 21220508
2010 CRL4(Cdt2) targets Set8 for ubiquitylation and proteasomal degradation in S phase through a degron that binds PCNA. Inactivation of CRL4(Cdt2) leads to Set8 stabilization and aberrant H4K20me1 accumulation in replicating cells. Expression of a degron-mutant Set8 causes premature H4K20me1 accumulation, chromatin compaction, and checkpoint-mediated G2 arrest. Ubiquitylation assay, CRL4(Cdt2) inactivation, Set8 degron mutant overexpression, cell cycle analysis Molecular cell High 20932472
2010 PR-Set7 regulates replication origins: onset of replication licensing coincides with increased H4K20me1 at origins by PR-Set7. Tethering PR-Set7 to a genomic locus promotes pre-RC loading. PR-Set7 undergoes PCNA- and Cul4-Ddb1-dependent degradation during S phase, causing H4K20me1 loss at origins. A degradation-resistant PR-Set7 mutant causes re-replication. ChIP, artificial tethering assay, protein stability assay, BrdU incorporation/re-replication assay Nature cell biology High 20953199
2010 PR-Set7 phosphorylation at Ser29 by CDK1/cyclinB during prophase through early anaphase removes PR-Set7 from mitotic chromosomes without affecting methyltransferase activity. S29 phosphorylation stabilizes PR-Set7 by inhibiting APC interaction. Dephosphorylation of S29 by Cdc14 phosphatases during late mitosis is required for APC(Cdh1)-mediated ubiquitination and proteolysis of PR-Set7. In vitro kinase assay, co-immunoprecipitation, phospho-specific antibody, dominant phospho-mutant analysis Genes & development High 20966048
2011 SET8 is physically associated with TWIST and promotes epithelial-mesenchymal transition (EMT) in breast cancer cells. SET8 acts as a dual epigenetic modifier on E-cadherin and N-cadherin promoters via H4K20 monomethylation activity. SET8 and TWIST are functionally interdependent for EMT and invasion. Co-immunoprecipitation, ChIP, RNAi knockdown, invasion assay, in vivo xenograft The EMBO journal Medium 21983900
2012 SETD8 methylates PCNA at lysine 248. This methylation stabilizes PCNA expression and significantly enhances the interaction between PCNA and the flap endonuclease FEN1. Loss of PCNA methylation retards Okazaki fragment maturation and slows DNA replication. In vitro methyltransferase assay, K248 mutant analysis, co-immunoprecipitation, Okazaki fragment assay Cancer research High 22556262
2012 PR-Set7 role in replication licensing is dependent on Suv4-20h1/2 activity. Aberrant rereplication from PR-Set7 stabilization correlates with decreased H4K20me1 and increased H4K20me3. PR-Set7 tethering to an artificial locus recruits the ORC in a manner dependent on Suv4-20h and H4K20me3, consistent with ORC1 and ORCA/LRWD1 binding properties toward H4K20 methylation. Genetic epistasis (conditional mouse knockout), artificial tethering assay, ChIP, re-replication assay Genes & development High 23152447
2012 SET8 has a recognition sequence covering seven amino acids (R17-H18-R19/K/Y-K20-V/I/L/F/Y-L/F/Y-R23). Symmetric and asymmetric methylation on R17 inhibits SET8-mediated H4K20 methylation. Dimethylation of R at the -3 position also reduces p53 K382 methylation by SET8. SET8's long recognition sequence restricts methylation of lysines in folded protein regions. Peptide array methylation assay, Celluspots array, in vitro methyltransferase assay Biochimie Medium 22583696
2013 Set8 monomethylates Numb in its PTB domain. Methylation of Numb by Set8 uncouples Numb from p53, leading to increased p53 ubiquitination and degradation. Set8-mediated Numb methylation abolishes the apoptotic function of Numb. Doxorubicin-induced reduction of Set8 enhances Numb-p53 interaction and apoptosis. In vitro methyltransferase assay, co-immunoprecipitation, Numb methylation-site mutant, apoptosis assay, RNAi Molecular cell High 23706821
2013 CRL1-FBXO11 ubiquitylates and degrades Cdt2 (the substrate receptor for CRL4(Cdt2)), thereby stabilizing Set8. Stabilization of Set8 by CRL1(FBXO11)-mediated Cdt2 degradation turns off TGF-β-activated Smad2 signaling and promotes epithelial cell migration. Co-immunoprecipitation, ubiquitination assay, RNAi, cell migration assay Molecular cell Medium 23478445
2014 SET8 acts directly at DNA double-strand breaks (DSBs) during the DNA damage response. SET8 accumulates at DSBs and is enzymatically active at DSBs. Depletion of SET8 abrogates 53BP1 accumulation at DSBs. SET8 occupancy at DSBs is regulated by HDACs. SET8 is functionally required for efficient DSB repair specifically via NHEJ. Laser microirradiation/ChIP-seq at DSBs, enzymatic activity assay at damage sites, HDAC inhibitor treatment, NHEJ reporter assay EMBO reports Medium 25252681
2014 PR-Set7 directly binds the C-terminus of the Riz1/PRDM2/KMT8 tumor suppressor; the N-terminal PR/SET domain of Riz1 preferentially monomethylates H3K9. The PR-Set7 binding domain is required for Riz1 nuclear localization and maintenance of the H4K20me1-H3K9me1 trans-tail histone code. Co-immunoprecipitation, in vitro pulldown, in vitro methyltransferase assay, cell fractionation Nucleic acids research Medium 24423864
2014 PR-SET7/SETD8 H4K20me1 controls RNA Pol II pausing dynamics. H4K20me1 is necessary for MSL complex recruitment and subsequent H4K16 acetylation, enabling Pol II release into active elongation. H4K20me1 is also required for H4K20me3 at paused genes. RNAi knockdown, ChIP, Pol II pausing analysis The Journal of biological chemistry Medium 24459145
2015 SCF(β-TRCP) promotes Set8 ubiquitination and degradation in a casein kinase I-dependent manner in response to DNA damage. Both CRL4(Cdt2) and SCF(β-TRCP) contribute to UV-induced Set8 degradation to control cell cycle progression and DNA damage checkpoints. Co-immunoprecipitation, in vitro ubiquitination assay, kinase assay, Set8 mutant stability assay Nature communications High 26666832
2016 Structural analysis of SETD8 using diverse X-ray structures (including covalent inhibitor-bound) and Markov state models from distributed MD simulations revealed that slow conformational motions of the enzyme are relevant to catalysis. A cysteine residue near the inhibitor binding site was identified for covalent modification, and a cocrystal structure of SETD8 with a small-molecule inhibitor was solved, providing the first atomic-level view of small-molecule inhibition. X-ray crystallography (multiple structures including inhibitor-bound), molecular dynamics simulation, Markov state modeling Journal of medicinal chemistry / eLife High 27804297 31081496
2016 Set8 uses multivalent interactions to bind the nucleosome: the i-SET and c-SET domains engage nucleosomal DNA 1-1.5 turns from the dyad, positioning the SET domain for H4K20 catalysis. A basic N-terminal extension makes an arginine anchor interaction with the H2A/H2B acidic patch. PCNA and the nucleosome compete for binding to Set8 through this N-terminal extension, providing a mechanism for how nucleosome binding protects Set8 from PCNA-dependent degradation. X-ray crystallography, solution binding studies, mutational analysis of Set8/nucleosome interface Journal of molecular biology High 26953260
2016 Kinetic isotope effect (KIE) measurements using MALDI-TOF MS revealed that SET8-catalyzed H4K20 monomethylation proceeds through an early, asymmetrical SN2 transition state with C-N and C-S distances of 2.35-2.40 Å and 2.00-2.05 Å, respectively. MALDI-TOF mass spectrometry-based KIE measurement, QM/MM computational modeling, kinetic isotope effect analysis Proceedings of the National Academy of Sciences of the United States of America High 27940912
2019 SET8 methylates UHRF1 at lysine 385, leading to ubiquitin-dependent degradation of UHRF1. LSD1 demethylates and stabilizes UHRF1. SET8 and LSD1 oppositely regulate global DNA methylation, primarily through controlling UHRF1 levels. UHRF1 downregulation in G2/M by SET8 suppresses DNMT1-mediated methylation on post-replicated DNA. In vitro methyltransferase assay, co-immunoprecipitation, ubiquitination assay, UHRF1 methylation-site mutant, bisulfite sequencing Nucleic acids research High 31400111
2019 USP17 deubiquitinates and stabilizes the SET8 protein. USP17 interacts with SET8 and removes polyubiquitin chains from SET8. USP17 knockdown decreases SET8 protein levels and H4K20 monomethylation, increases p21 levels, and suppresses cell proliferation, triggering cellular senescence. Co-immunoprecipitation, in vitro deubiquitination assay, RNAi knockdown, cell proliferation/senescence assay The Journal of biological chemistry Medium 31533987
2020 KMT5A/SET8 methylates α-tubulin at lysine 311. The transcription factor LSF/CP2 binds both α-tubulin and SET8 and enhances SET8-mediated α-tubulin methylation in vitro. The LSF inhibitor FQI1 counters LSF-facilitated tubulin methylation. In vitro radiolabeling, mass spectrometry, co-immunoprecipitation, immunofluorescence, pulldown assay The Journal of biological chemistry Medium 32111740
2022 KMT5A monomethylates SNIP1 at K301. This methylation releases histone acetyltransferase KAT2A and promotes the interaction of c-MYC and KAT2A, leading to recruitment of the c-MYC/KAT2A complex to c-MYC target promoters. This inhibits the Hippo kinase cascade and transcriptionally activates MARK4, enhancing TNBC metastasis. In vitro methyltransferase assay, Co-immunoprecipitation, ChIP, SNIP1 K301 mutant analysis, in vivo xenograft Nature communications Medium 35449131
2017 SETD8 ablation in neuroblastoma rescues p53 pro-apoptotic and cell-cycle arrest functions by decreasing p53K382me1, activating the p53 canonical pathway. Pharmacological inhibition with UNC0379 conferred survival advantage in xenograft NB models. RNAi screen, chemical screen, p53K382me1 immunoblot, xenograft model Cancer cell Medium 28073004
2023 PR-SET7 deficiency in trophoblasts derepresses endogenous retroviruses (ERVs), causing double-stranded RNA stress and viral mimicry response that drives interferon response and necroptosis. H4K20me1 and H4K20me3 mediate suppression of ERV expression in trophoblasts. PR-SET7 deficiency in mice leads to defective trophoblasts and early embryonic loss. Conditional mouse knockout, RNA-seq, ChIP, interferon signaling assays, necroptosis assay Proceedings of the National Academy of Sciences of the United States of America Medium 37307441
2008 QM/MM computational analysis of SET8 catalysis revealed that the methylation reaction requires prior deprotonation of the target lysine, and that product specificity (monomethylation) results from a methyl substituent on the product blocking formation of a water channel required for subsequent deprotonation, preventing a second methylation. QM/MM molecular dynamics simulation, kinetic analysis Biochemistry Medium 18512960
2013 MBTD1 associates with Pr-Set7 in mouse oocytes (demonstrated by co-IP). MBTD1 depletion reduces Pr-Set7 expression and H4K20me1 levels, causes DNA damage, and recapitulates phenotypes of Pr-Set7 depletion in oocyte meiotic maturation. Co-immunoprecipitation, RNAi knockdown, immunofluorescence Cell cycle Low 23475131
2020 STRA8 and SETD8 interact (yeast two-hybrid, confirmed by co-IP); SETD8 negatively regulates STRA8 promoter transcriptional activity. STRA8 increases SETD8 promoter activity in a dose-dependent manner. Both show cell cycle-dependent expression in germline cells, co-localizing with PCNA in spermatogonia. Yeast two-hybrid, co-immunoprecipitation, luciferase reporter assay, immunofluorescence Journal of cellular and molecular medicine Low 32090428
2015 SetD8 is a context-dependent GATA-1 corepressor in erythroid cells. SetD8 catalyzes H4K20me1 at a critical Gata2 cis-element and restricts Scl/TAL1 occupancy at the Gata2 enhancer, thereby repressing Gata2 transcription. Loss of SetD8 impairs erythroblast maturation and survival. shRNA knockdown, ChIP, erythroblast maturation assay, co-immunoprecipitation Molecular and cellular biology Medium 25855754
2020 SETD8 interacts with STAT3 and is recruited by STAT3 to the DUSP10 promoter, epigenetically silencing DUSP10 expression via H4K20me1. Decreased DUSP10 (an ERK1/2 phosphatase) potentiates constitutive ERK1/2 activation in pancreatic cancer. Mass spectrometry, co-immunoprecipitation, ChIP, luciferase reporter assay, RNAi Cancer letters Medium 33232789

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Molecular cell 490 12086618
2007 Modulation of p53 function by SET8-mediated methylation at lysine 382. Molecular cell 369 17707234
2002 Purification and functional characterization of SET8, a nucleosomal histone H4-lysine 20-specific methyltransferase. Current biology : CB 291 12121615
2012 PR-Set7 and H4K20me1: at the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription. Genes & development 278 22345514
2010 The histone H4 Lys 20 methyltransferase PR-Set7 regulates replication origins in mammalian cells. Nature cell biology 226 20953199
2011 SET8 promotes epithelial-mesenchymal transition and confers TWIST dual transcriptional activities. The EMBO journal 213 21983900
2005 Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase. Genes & development 205 15933070
2010 Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)-mediated PCNA-dependent degradation during DNA damage. Molecular cell 204 21035370
2010 CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. Molecular cell 188 20932472
2007 The histone methyltransferase SET8 is required for S-phase progression. The Journal of cell biology 188 18166648
2012 Histone lysine methyltransferase SETD8 promotes carcinogenesis by deregulating PCNA expression. Cancer research 172 22556262
2009 The peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha heterodimer targets the histone modification enzyme PR-Set7/Setd8 gene and regulates adipogenesis through a positive feedback loop. Molecular and cellular biology 160 19414603
2005 Specificity and mechanism of the histone methyltransferase Pr-Set7. Genes & development 159 15933069
2007 PR-Set7-dependent lysine methylation ensures genome replication and stability through S phase. The Journal of cell biology 139 18158331
2008 Catalytic function of the PR-Set7 histone H4 lysine 20 monomethyltransferase is essential for mitotic entry and genomic stability. The Journal of biological chemistry 129 18480059
2010 Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression. Genes & development 110 20966048
2008 Direct interaction between SET8 and proliferating cell nuclear antigen couples H4-K20 methylation with DNA replication. The Journal of biological chemistry 105 18319261
2011 SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation. The Journal of cell biology 101 21220508
2012 The role of PR-Set7 in replication licensing depends on Suv4-20h. Genes & development 98 23152447
2009 An miR-502-binding site single-nucleotide polymorphism in the 3'-untranslated region of the SET8 gene is associated with early age of breast cancer onset. Clinical cancer research : an official journal of the American Association for Cancer Research 95 19789321
2017 Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma. Cancer cell 92 28073004
2013 Dynamic methylation of Numb by Set8 regulates its binding to p53 and apoptosis. Molecular cell 87 23706821
2014 Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8. Journal of medicinal chemistry 86 25032507
2016 The emerging role of lysine methyltransferase SETD8 in human diseases. Clinical epigenetics 75 27688818
2011 The histone methyltransferase Setd8 acts in concert with c-Myc and is required to maintain skin. The EMBO journal 73 22117221
2019 SET8 prevents excessive DNA methylation by methylation-mediated degradation of UHRF1 and DNMT1. Nucleic acids research 71 31400111
2010 The MBT repeats of L3MBTL1 link SET8-mediated p53 methylation at lysine 382 to target gene repression. The Journal of biological chemistry 71 20870725
2013 CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration. Molecular cell 69 23478445
2010 PR-Set7-mediated monomethylation of histone H4 lysine 20 at specific genomic regions induces transcriptional repression. Journal of cellular biochemistry 64 20512922
2016 Inactivation of the CRL4-CDT2-SET8/p21 ubiquitylation and degradation axis underlies the therapeutic efficacy of pevonedistat in melanoma. EBioMedicine 61 27333051
2010 IUGR decreases PPARγ and SETD8 Expression in neonatal rat lung and these effects are ameliorated by maternal DHA supplementation. Early human development 60 20869820
2014 SET8 methyltransferase activity during the DNA double-strand break response is required for recruitment of 53BP1. EMBO reports 59 25252681
2008 PR-SET7 and SUV4-20H regulate H4 lysine-20 methylation at imprinting control regions in the mouse. EMBO reports 59 18724273
2007 SET8-mediated methylations of histone H4 lysine 20 mark silent heterochromatic domains in apicomplexan genomes. Molecular and cellular biology 59 17562855
2014 Small-molecule inhibitors of SETD8 with cellular activity. ACS chemical biology 57 25137013
2022 KMT5A-methylated SNIP1 promotes triple-negative breast cancer metastasis by activating YAP signaling. Nature communications 50 35449131
2017 The SETD8/PR-Set7 Methyltransferase Functions as a Barrier to Prevent Senescence-Associated Metabolic Remodeling. Cell reports 48 28249161
2018 Histone methyltransferase KMT5A gene modulates oncogenesis and lipid metabolism of papillary thyroid cancer in vitro. Oncology reports 46 29512765
2011 A new regulator of the cell cycle: the PR-Set7 histone methyltransferase. Cell cycle (Georgetown, Tex.) 45 21200139
2015 MicroRNA-127-3p inhibits proliferation and invasion by targeting SETD8 in human osteosarcoma cells. Biochemical and biophysical research communications 44 26707641
2011 Coupling mitosis to DNA replication: the emerging role of the histone H4-lysine 20 methyltransferase PR-Set7. Trends in cell biology 43 21632252
2019 Monomethyltransferase SET8 facilitates hepatocellular carcinoma growth by enhancing aerobic glycolysis. Cell death & disease 42 30952833
2019 The dynamic conformational landscape of the protein methyltransferase SETD8. eLife 42 31081496
2013 microRNA-7 suppresses the invasive potential of breast cancer cells and sensitizes cells to DNA damages by targeting histone methyltransferase SET8. The Journal of biological chemistry 41 23720754
2014 Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR-SET7-deficient livers. The EMBO journal 40 25515659
2021 KMT5A downregulation participated in High Glucose-mediated EndMT via Upregulation of ENO1 Expression in Diabetic Nephropathy. International journal of biological sciences 39 34803485
2015 SCF(β-TRCP) promotes cell growth by targeting PR-Set7/Set8 for degradation. Nature communications 38 26666832
2014 A dual role for the histone methyltransferase PR-SET7/SETD8 and histone H4 lysine 20 monomethylation in the local regulation of RNA polymerase II pausing. The Journal of biological chemistry 37 24459145
2016 miR-382 inhibits tumor progression by targeting SETD8 in non-small cell lung cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 28006750
2015 SET8 induces epithelial‑mesenchymal transition and enhances prostate cancer cell metastasis by cooperating with ZEB1. Molecular medicine reports 35 26717907
2016 MiR-502/SET8 regulatory circuit in pathobiology of breast cancer. Cancer letters 34 27080302
2020 High Glucose Induces Endothelial COX2 and iNOS Expression via Inhibition of Monomethyltransferase SETD8 Expression. Journal of diabetes research 33 32185234
2016 Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase. Journal of medicinal chemistry 33 27804297
2012 The SET8 H4K20 protein lysine methyltransferase has a long recognition sequence covering seven amino acid residues. Biochimie 33 22583696
2005 SET8 recognizes the sequence RHRK20VLRDN within the N terminus of histone H4 and mono-methylates lysine 20. The Journal of biological chemistry 33 15964846
2017 Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions. Cell reports 32 28746875
2014 Histone H4 Lys 20 methyltransferase SET8 promotes androgen receptor-mediated transcription activation in prostate cancer. Biochemical and biophysical research communications 32 24937452
2015 Epigenetic Determinants of Erythropoiesis: Role of the Histone Methyltransferase SetD8 in Promoting Erythroid Cell Maturation and Survival. Molecular and cellular biology 31 25855754
2021 LncRNA LINC00473 is involved in the progression of invasive pituitary adenoma by upregulating KMT5A via ceRNA-mediated miR-502-3p evasion. Cell death & disease 30 34091587
2017 Monomethyltransferase SETD8 regulates breast cancer metabolism via stabilizing hypoxia-inducible factor 1α. Cancer letters 30 28089831
2016 miR-502 medaited histone methyltransferase SET8 expression is associated with outcome of esophageal squamous cell carcinoma. Scientific reports 30 27605386
2021 The CREB/KMT5A complex regulates PTP1B to modulate high glucose-induced endothelial inflammatory factor levels in diabetic nephropathy. Cell death & disease 29 33782381
2021 ets1 associates with KMT5A to participate in high glucose-mediated EndMT via upregulation of PFN2 expression in diabetic nephropathy. Molecular medicine (Cambridge, Mass.) 29 34238215
2013 Genetic variation in a microRNA-502 minding site in SET8 gene confers clinical outcome of non-small cell lung cancer in a Chinese population. PloS one 29 24146953
2019 Combined functional genomic and chemical screens identify SETD8 as a therapeutic target in MYC-driven medulloblastoma. JCI insight 27 30626740
2017 The Methyltransferase Setd8 Is Essential for Erythroblast Survival and Maturation. Cell reports 27 29186677
2016 Multivalent Interactions by the Set8 Histone Methyltransferase With Its Nucleosome Substrate. Journal of molecular biology 27 26953260
2016 Kinetic isotope effects reveal early transition state of protein lysine methyltransferase SET8. Proceedings of the National Academy of Sciences of the United States of America 27 27940912
2013 MBTD1 is associated with Pr-Set7 to stabilize H4K20me1 in mouse oocyte meiotic maturation. Cell cycle (Georgetown, Tex.) 27 23475131
2020 SETD8 potentiates constitutive ERK1/2 activation via epigenetically silencing DUSP10 expression in pancreatic cancer. Cancer letters 26 33232789
2019 The ubiquitin-specific protease USP17 prevents cellular senescence by stabilizing the methyltransferase SET8 and transcriptionally repressing p21. The Journal of biological chemistry 26 31533987
2017 The PPARγ-SETD8 axis constitutes an epigenetic, p53-independent checkpoint on p21-mediated cellular senescence. Aging cell 26 28514051
2016 Methylation of histone H4 lysine 20 by PR-Set7 ensures the integrity of late replicating sequence domains in Drosophila. Nucleic acids research 26 27131378
2014 The PR-Set7 binding domain of Riz1 is required for the H4K20me1-H3K9me1 trans-tail 'histone code' and Riz1 tumor suppressor function. Nucleic acids research 26 24423864
2014 Structure-activity relationship studies of SETD8 inhibitors. MedChemComm 26 25554733
2022 The SETD8/ELK1/bach1 complex regulates hyperglycaemia-mediated EndMT in diabetic nephropathy. Journal of translational medicine 25 35351142
2020 SET8 suppression mediates high glucose-induced vascular endothelial inflammation via the upregulation of PTEN. Experimental & molecular medicine 25 33028948
2020 Histone methyltransferase SET8 is regulated by miR-192/215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells. Cell death & disease 25 33127874
2015 Histone methyltransferase Setd8 represses Gata2 expression and regulates erythroid maturation. Molecular and cellular biology 25 25848090
2014 IUGR disrupts the PPARγ-Setd8-H4K20me(1) and Wnt signaling pathways in the juvenile rat hippocampus. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 25 25107645
2008 PR-Set7 establishes a repressive trans-tail histone code that regulates differentiation. Molecular and cellular biology 25 18474616
2021 SET8 mitigates hepatic ischemia/reperfusion injury in mice by suppressing MARK4/NLRP3 inflammasome pathway. Life sciences 24 33662429
2021 SETD8 stabilized by USP17 epigenetically activates SREBP1 pathway to drive lipogenesis and oncogenesis of ccRCC. Cancer letters 24 34942305
2020 Downregulation of histone methyltransferase SET8 inhibits progression of hepatocellular carcinoma. Scientific reports 24 32161353
2018 SET8 is involved in the regulation of hyperglycemic memory in human umbilical endothelial cells. Acta biochimica et biophysica Sinica 24 29762637
2018 mir-127-3p inhibits the proliferation of myocytes by targeting KMT5a. Biochemical and biophysical research communications 24 29932923
2012 Identification of PR-SET7 and EZH2 selective inhibitors inducing cell death in human leukemia U937 cells. Biochimie 24 22709867
2022 Roles for the methyltransferase SETD8 in DNA damage repair. Clinical epigenetics 23 35246238
2021 Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma. Clinical epigenetics 23 34530900
2020 Meiotic gatekeeper STRA8 regulates cell cycle by interacting with SETD8 during spermatogenesis. Journal of cellular and molecular medicine 23 32090428
2020 The histone methyltransferase Setd8 alters the chromatin landscape and regulates the expression of key transcription factors during erythroid differentiation. Epigenetics & chromatin 22 32178723
2013 Association of miR-502-binding site single nucleotide polymorphism in the 3'-untranslated region of SET8 and TP53 codon 72 polymorphism with non-small cell lung cancer in Chinese population. Acta biochimica et biophysica Sinica 22 24374662
2008 Product specificity and mechanism of protein lysine methyltransferases: insights from the histone lysine methyltransferase SET8. Biochemistry 22 18512960
2023 Trophoblast PR-SET7 dysfunction induces viral mimicry response and necroptosis associated with recurrent miscarriage. Proceedings of the National Academy of Sciences of the United States of America 21 37307441
2021 Histone lysine methyltransferase Pr-set7/SETD8 promotes neural stem cell reactivation. EMBO reports 21 33565211
2020 The microtubule-associated histone methyltransferase SET8, facilitated by transcription factor LSF, methylates α-tubulin. The Journal of biological chemistry 21 32111740
2020 Epigenetic Modifier SETD8 as a Therapeutic Target for High-Grade Serous Ovarian Cancer. Biomolecules 20 33339442
2018 Downregulation of SETD8 by miR-382 is involved in glioma progression. Pathology, research and practice 19 29487005
2017 PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice. Cell death and differentiation 19 28731465
2016 Progress in the Development of Lysine Methyltransferase SETD8 Inhibitors. ChemMedChem 18 27411844

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