Affinage

KDM8

Bifunctional peptidase and arginyl-hydroxylase JMJD5 · UniProt Q8N371

Length
416 aa
Mass
47.3 kDa
Annotated
2026-06-10
43 papers in source corpus 29 papers cited in narrative 29 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

KDM8/JMJD5 is a JmjC-domain 2-oxoglutarate- and Fe(II)-dependent oxygenase that regulates cell cycle progression, chromatin state, metabolism, and genome stability (PMID:20457893, PMID:29563586). Although it was first described as an H3K36me2 demethylase that activates cyclin A1 transcription and is required for proliferation (PMID:20457893), high-resolution crystal structures and biochemical assays established that its catalytic domain is structurally homologous to protein hydroxylases (FIH-1, JMJD6) rather than lysine demethylases and lacks intrinsic demethylase activity (PMID:22851697, PMID:24100311). Its bona fide enzymatic activities are stereoselective C-3 hydroxylation of arginine residues in substrates including RCCD1, RPS6, and ISY1 [PMID:29563586, PMID:bio_10.1101_2025.09.27.678987], and divalent-cation-dependent proteolysis of arginine-methylated and monomethyl-lysine histone tails, with cleavage enriched at JMJD5-bound promoters and coupled to release of paused RNA Pol II via binding to the CDK9-phosphorylated CTD (PMID:28847961, PMID:28982940, PMID:32747552). Despite lacking demethylase activity, KDM8 controls cellular H3K36me2 levels in vivo, repressing growth-arrest and tissue-specific gene programs: it limits Cdkn1a/p21 expression to permit embryonic and stem-cell proliferation (PMID:22241836, PMID:24740926), and in cardiomyocytes it represses TBX15 to sustain NAD+ biosynthesis and mitochondrial gene networks, with its loss causing dilated cardiomyopathy rescuable by NAD+ supplementation (PMID:38665902). As a protein hydroxylase it triggers VHL-dependent degradation of NFATc1 in osteoclastogenesis (PMID:22375008), and it acts as a non-enzymatic scaffold/coactivator by binding the p53 DNA-binding domain to restrain p53 target gene activation (PMID:26025680, PMID:26334721), by interacting with PKM2 to block its tetramerization and drive nuclear HIF-1α coactivation of glycolytic genes (PMID:24344305, PMID:30072740), and by facilitating proteasomal turnover of CRY1 (FBXL3-dependent) to tune circadian oscillations and of EGFR (HUWE1-dependent) in lung cancer (PMID:30500822, PMID:37813845). KDM8 additionally stabilizes mitotic spindle microtubules through tubulin association and MAP1B regulation (PMID:26710852, PMID:27715397) and modulates DNA double-strand break repair pathway choice, interacting directly with RAD51 and the JMJD5:RCCD1 complex to suppress replication stress [PMID:28207814, PMID:42001401, PMID:bio_10.1101_2025.11.22.689938].

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2010 High

    Established KDM8 as a chromatin-associated regulator of cell cycle gene transcription, initially attributing this to H3K36me2 demethylase activity at cyclin A1.

    Evidence ChIP-chip, demethylase assay, and siRNA loss-of-function in MCF7 cells

    PMID:20457893

    Open questions at the time
    • In vitro demethylase activity was later contested
    • Mechanism by which it lowers H3K36me2 without intrinsic demethylase activity unresolved
  2. 2012 High

    Redefined the catalytic identity of JMJD5 by showing its fold matches protein hydroxylases, not lysine demethylases, and that it lacks demethylase activity in vitro.

    Evidence X-ray crystallography with 2-OG/NOG plus in vitro demethylase assays

    PMID:22851697 PMID:24100311

    Open questions at the time
    • Physiological hydroxylation substrate not identified at this stage
    • How it regulates H3K36me2 in cells without demethylase activity unexplained
  3. 2012 High

    Demonstrated in vivo that JMJD5 is essential for embryonic proliferation by restraining Cdkn1a/p21, linking the gene to growth control through genetic epistasis.

    Evidence Knockout mice, ChIP, and Jmjd5/Cdkn1a double-knockout rescue

    PMID:22241836

    Open questions at the time
    • Molecular basis of Cdkn1a regulation (direct vs indirect) not fully defined
    • Mid-gestation lethality only partially rescued
  4. 2012 High

    Provided the first physiological example of JMJD5 protein hydroxylase output by linking NFATc1 hydroxylation to VHL-mediated degradation.

    Evidence In vitro hydroxylase assay, Co-IP with VHL, proteasome inhibition in osteoclast differentiation

    PMID:22375008

    Open questions at the time
    • Exact hydroxylated residue on NFATc1 not mapped
    • Generality to other VHL substrates unknown
  5. 2013 High

    Expanded KDM8 into metabolic control by showing it binds PKM2 to block tetramerization and drive nuclear HIF-1α coactivation of glycolytic genes.

    Evidence Co-IP, domain mapping, pyruvate kinase assay, ChIP and metabolic readouts

    PMID:24344305

    Open questions at the time
    • Whether the PKM2 interaction requires catalytic activity not established
    • Stoichiometry of complex unknown
  6. 2013 Medium

    Defined nucleocytoplasmic shuttling determinants showing both NLS and JmjC domain are required for chromatin function.

    Evidence Deletion mutagenesis, fractionation, Co-IP with importins, ChIP

    PMID:23948433

    Open questions at the time
    • Single lab
    • Regulation of shuttling under signaling not addressed
  7. 2014 Medium

    Extended the proliferation role to human pluripotency, showing the JMJD5/CDKN1A axis maintains the stem-cell state.

    Evidence shRNA knockdown, cell cycle and differentiation assays, double-knockdown epistasis in hESCs

    PMID:24740926

    Open questions at the time
    • Direct molecular mechanism at CDKN1A not resolved
    • Single lab
  8. 2015 Medium

    Identified a non-enzymatic scaffolding mechanism whereby JMJD5 binds the p53 DBD to restrain p53 target activation, modulated by DNA damage.

    Evidence Co-IP, domain mapping, ChIP and cell cycle analysis in cells and mouse embryos

    PMID:26025680 PMID:26334721

    Open questions at the time
    • Whether catalytic activity contributes to p53 control unclear
    • Single lab for each system
  9. 2015 Medium

    Revealed a mitotic function in spindle microtubule stabilization and checkpoint satisfaction via tubulin association.

    Evidence Immunofluorescence, Co-IP with tubulin, siRNA, live imaging, SAC rescue

    PMID:26710852

    Open questions at the time
    • Whether tubulin/microtubule effects are enzymatic unknown
    • Single lab
  10. 2016 Medium

    Showed JMJD5 enhances CDKN1A transcription independently of demethylase activity and that its hydroxylase activity supports HBx-mediated HBV replication, broadening its regulatory and viral roles.

    Evidence ChIP, catalytic mutant analysis, knockout/complementation, Co-IP in HCC and HBV systems

    PMID:26760772 PMID:26792738

    Open questions at the time
    • Context-dependent direction of CDKN1A regulation (activator vs repressor) unreconciled
    • Direct hydroxylation target in HBV context not identified
  11. 2016 Medium

    Linked JMJD5 to microtubule stability through MAP1B regulation, with therapeutic relevance to microtubule-targeting agents.

    Evidence siRNA, immunofluorescence, nocodazole sensitivity, MAP1B rescue

    PMID:27715397

    Open questions at the time
    • Mechanism connecting JMJD5 to MAP1B levels unknown
    • Single lab
  12. 2017 High

    Established the protease identity of JMJD5, showing it cleaves methylated-arginine and monomethyl-lysine histone tails, providing a mechanism for histone tail removal and a basis for its effects on chromatin.

    Evidence In vitro protease assays with histone peptides, mass spectrometry, deficient fibroblasts, ChIP under DNA damage

    PMID:28847961 PMID:28982940

    Open questions at the time
    • In vivo abundance and genomic scope of histone clipping not fully quantified
    • Relationship between proteolysis and arginine hydroxylase activity unclear
  13. 2017 High

    Demonstrated conserved control of H3K36me2 is required for late homologous recombination and genome maintenance in C. elegans.

    Evidence C. elegans knockout, catalytic mutant phenocopy, genetic epistasis, RAD-51 immunostaining, IR sensitivity

    PMID:28207814

    Open questions at the time
    • Direct enzymatic substrate underlying H3K36me2 change in worm not defined
    • Conservation of HR role to human only later addressed
  14. 2017 Medium

    Placed Kdm8 within a transcriptional circuit (Miz1 repression) controlling Schwann cell quiescence and peripheral nerve homeostasis.

    Evidence RNA-seq, ChIP, Miz1ΔPOZ transgenic mouse, cell cycle analysis

    PMID:29217679

    Open questions at the time
    • Direct vs indirect H3K36me2 changes at cell cycle loci unresolved
    • Single lab
  15. 2018 High

    Identified the true enzymatic activity as stereoselective arginine C-3 hydroxylation with defined substrates and structural basis, resolving the long-standing catalytic ambiguity.

    Evidence Peptide screening, in vitro hydroxylase assay with MS, X-ray crystallography of RCCD1/RPS6 substrate features

    PMID:29459673 PMID:29563586

    Open questions at the time
    • Full physiological substrate repertoire incomplete
    • Functional consequences of RPS6 hydroxylation not established
  16. 2018 Medium

    Showed dual coactivator roles in prostate cancer and a conserved circadian function, integrating KDM8 into androgen and clock signaling through protein-protein interactions and substrate degradation.

    Evidence Co-IP, shRNA, ChIP for AR/PKM2; Co-IP, knockout, proteasome and circadian reporter assays for CRY1/FBXL3

    PMID:30072740 PMID:30500822

    Open questions at the time
    • Whether AR coactivation requires catalysis unknown
    • How JMJD5 mechanistically promotes CRY1 proteasome targeting not fully defined
  17. 2020 High

    Connected histone clipping to transcriptional elongation by showing CDK9-phosphorylated Pol II CTD recruits JMJD5 to the +1 nucleosome to release Pol II pausing.

    Evidence Knockout, ChIP-seq, Co-IP with phospho-CTD peptides, RNA-seq

    PMID:32747552

    Open questions at the time
    • Direct demonstration of in vivo +1 nucleosome clipping events limited
    • Genome-wide rules for JMJD5 recruitment incomplete
  18. 2023 High

    Demonstrated a tissue-specific metabolic role in heart, where KDM8 represses TBX15 to maintain NAD+ biosynthesis and prevent dilated cardiomyopathy.

    Evidence Cardiomyocyte-specific knockout, ChIP-seq, RNA-seq, NAD+ supplementation and TBX15 overexpression rescue, echocardiography

    PMID:38665902

    Open questions at the time
    • Enzymatic basis of H3K36me2 lowering at TBX15 not biochemically reconciled with hydroxylase identity
  19. 2023 Medium

    Identified a tumor-suppressive degradation function targeting EGFR via HUWE1 and showed JMJD5 can be transferred between cells in extracellular vesicles.

    Evidence Co-IP, proteasome inhibition, siRNA, EV isolation, xenograft models in NSCLC

    PMID:37813845

    Open questions at the time
    • Whether EGFR destabilization requires catalytic activity unknown
    • Single lab
  20. 2022 Medium

    Defined an upstream regulatory input showing phosphorylation of JMJD5 Ser361 by a circHEATR5B-encoded protein destabilizes it, linking JMJD5 stability to glycolytic control in glioblastoma.

    Evidence Mass spectrometry, Co-IP, phospho-site mapping, siRNA, glycolysis assays, xenograft

    PMID:35538499

    Open questions at the time
    • Kinase responsible for Ser361 phosphorylation not identified
    • Single lab
  21. 2025 Medium

    Proposed a principal effector pathway in which JMJD5 hydroxylates ISY1, which then inhibits PRMT6, accounting for much of the molecular phenotype of JMJD5 loss.

    Evidence Hydroxylase assay, Co-IP, PRMT6 activity assay, siRNA epistasis, MS (preprint)

    PMID:bio_10.1101_2025.09.27.678987

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Specific ISY1 arginine residue and structural basis of PRMT6 inhibition not finalized
  22. 2025 Medium

    Implicated the JMJD5:RCCD1 complex in suppressing replication stress and supporting fork restart, with cancer mutations disrupting the interaction and hydroxylase activity.

    Evidence Structural analysis of cancer mutants, Co-IP, replication stress and fiber assays, RAD51-paralogue interaction mapping (preprint)

    PMID:bio_10.1101_2025.11.22.689938

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Mechanism by which hydroxylation prevents replication stress unresolved
  23. 2026 Medium

    Established KDM8 as a modulator of DNA double-strand break repair pathway choice with a direct, damage-induced interaction with RAD51.

    Evidence HR/NHEJ reporter assays, FRET in living cells, overexpression and knockdown

    PMID:42001401

    Open questions at the time
    • Demethylase-independent component of the effect mechanistically undefined
    • Functional consequence of KDM8-RAD51 interaction not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How KDM8's confirmed arginine hydroxylase and histone protease activities mechanistically produce its many cellular outputs — H3K36me2 regulation, p53/AR/PKM2 scaffolding, substrate degradation, and genome stability — remains to be unified.
  • No single biochemical mechanism reconciles its demethylase-independent control of H3K36me2 with its hydroxylase/protease catalysis
  • Which functions require catalysis versus scaffolding is unresolved across most contexts
  • Physiological substrate repertoire of arginine hydroxylation incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0140110 transcription regulator activity 5 GO:0016491 oxidoreductase activity 4 GO:0008092 cytoskeletal protein binding 2 GO:0016787 hydrolase activity 2 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 5 GO:0005694 chromosome 4 GO:0005829 cytosol 4 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 3 R-HSA-9909396 Circadian clock 1
Partners
ARCRY1HUWE1PKM2RAD51RCCD1TP53VHL
Complex memberships
JMJD5:RCCD1 complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 KDM8/JMJD5 demethylates H3K36me2 and occupies the coding region of cyclin A1, functioning as a transcriptional activator by inhibiting HDAC recruitment via demethylation of H3K36me2; loss-of-function in MCF7 cells leads to cell cycle arrest. Chromatin immunoprecipitation with genome tiling arrays, RNA microarray, histone demethylase assay, loss-of-function (siRNA) Proceedings of the National Academy of Sciences of the United States of America High 20457893
2012 Crystal structures of the human JMJD5 catalytic domain in complex with 2-oxoglutarate and N-oxalylglycine reveal a β-barrel fold conserved in the JmjC family and structural homology with protein hydroxylases FIH-1 and JMJD6 rather than lysine demethylases; biochemical assays showed JMJD5 does not display demethylase activity toward methylated H3K36 or other methyllysines, suggesting JMJD5 functions as a protein hydroxylase. High-resolution X-ray crystallography, in vitro demethylase biochemical assays Molecular and cellular biology High 22851697
2012 Jmjd5-knockout mice die at mid-gestation; Jmjd5-deficient MEFs and embryos show upregulation of Cdkn1a (p21); ChIP analysis showed increased H3K36me2 and reduced Jmjd5 occupancy in the transcribed region of Cdkn1a; genetic rescue by Cdkn1a knockout partially rescues growth retardation, establishing Jmjd5 as an epigenetic regulator of Cdkn1a expression controlling embryonic cell proliferation. Knockout mouse generation, ChIP, siRNA knockdown, double-knockout genetic epistasis Development (Cambridge, England) High 22241836
2012 JMJD5 regulates NFATc1 protein stability in osteoclastogenesis: JMJD5 hydroxylates NFATc1 (protein hydroxylase activity via JmjC domain) and induces its association with the E3 ubiquitin ligase VHL, facilitating proteasomal degradation of NFATc1 and thereby negatively regulating osteoclast differentiation. No histone demethylase activity was detected in vitro or in cells. Stable knockdown cells, osteoclast differentiation assay, in vitro hydroxylase assay, co-immunoprecipitation with VHL, proteasome inhibitor experiments The Journal of biological chemistry High 22375008
2013 JMJD5 interacts directly with PKM2 at the intersubunit interface region of PKM2, hindering PKM2 tetramerization and blocking pyruvate kinase activity; this interaction promotes PKM2 nuclear translocation and HIF-1α-mediated transactivation of glycolytic genes including LDH-A and PKM2. Co-immunoprecipitation, domain mapping, pyruvate kinase activity assay, knockdown/rescue, ChIP, glucose uptake and lactate assays Proceedings of the National Academy of Sciences of the United States of America High 24344305
2013 JMJD5 contains a functional bipartite nuclear localization signal (NLS) and a CRM1-dependent nuclear export signal (NES) in its N-terminal domain; importin α/β and transportin-1 were identified as transport proteins; both active NLS and JmjC domain are required for cyclin A1 transcription regulation and H3K36me2 demethylation at cyclin A1. Deletion mutagenesis, nuclear/cytoplasmic fractionation, co-immunoprecipitation with importins, ChIP Biochimie Medium 23948433
2013 Crystal structure of human JMJD5 (lacking N-terminal 175 residues) reveals that Gln275, Trp310, and Trp414 side chains may block methylated lysine insertion into the active center, suppressing histone demethylase activity; structural comparison with FIH suggests JMJD5 may function as a protein hydroxylase; interaction between JMJD5 and core histone octamer proteins was detected. X-ray crystallography, structural comparison Acta crystallographica. Section D, Biological crystallography Medium 24100311
2014 Depletion of JMJD5 in human ESCs causes G1 accumulation, loss of pluripotency, and differentiation; this phenotype is caused by upregulation of CDKN1A (p21), and co-depletion of both JMJD5 and CDKN1A rescues the rapid G1 phase and pluripotent state, establishing the JMJD5/CDKN1A axis as essential for hESC pluripotency. shRNA knockdown, cell cycle analysis, double knockdown epistasis, differentiation assays Stem cells (Dayton, Ohio) Medium 24740926
2015 JMJD5 forms a complex with the tumor suppressor p53 by interacting with the p53 DNA-binding domain (DBD) and negatively regulates p53 transcriptional activity; upon DNA damage, the JMJD5-p53 association decreases, promoting p53 recruitment to target genes including CDKN1A and P53R2; JMJD5 facilitates cell cycle progression in a p53-dependent manner. Co-immunoprecipitation, domain mapping, ChIP, knockdown with gene expression analysis, cell cycle analysis Biochimica et biophysica acta Medium 26025680
2015 JMJD5 partially localizes to mitotic spindles during mitosis; depletion of JMJD5 results in mitotic arrest, spindle assembly defects, sustained spindle assembly checkpoint (SAC) activation, reduced α-tubulin acetylation on spindles, and insufficient interkinetochore tension; JMJD5 interacts with tubulin proteins and associates with microtubules. Immunofluorescence, co-immunoprecipitation with tubulin, siRNA knockdown, live-cell imaging, SAC inactivation rescue experiments The Journal of biological chemistry Medium 26710852
2015 Jmjd5 regulates a subset of p53 target genes in mouse embryos; Jmjd5-deficient embryos show increased p53 recruitment at Cdkn1a, Pmaip1, and Mdm2 loci without increased Trp53 mRNA; genetic rescue by Trp53 knockout partially recovers growth defects, establishing Jmjd5 as a regulator upstream of p53 signaling. ChIP, qPCR, double-knockout genetic epistasis (Jmjd5/Trp53) Cell and tissue research Medium 26334721
2016 JMJD5 directly enhances CDKN1A transcription by binding to CDKN1A's promoter independently of H3K36me2 demethylase activity in TP53-null HCC cells; JMJD5 knockdown promotes HCC cell proliferation by downregulating CDKN1A; CDKN1A knockdown abrogates the anti-proliferative effect of JMJD5 overexpression. ChIP, siRNA knockdown, ectopic overexpression, catalytic mutant analysis, cell proliferation assays Oncotarget Medium 26760772
2016 JMJD5 interacts with the HBV protein HBx in the cytoplasm; JMJD5 hydroxylase activity regulates expression of hepatocyte transcription factors HNF4A, CEBPA, and FOXA3; the Gly135Glu mutation in JMJD5 abrogates binding with HBx and HBV replication rescue, establishing JMJD5 hydroxylase activity as required for HBx-mediated HBV replication. JMJD5 knockout cells, complementation, co-immunoprecipitation, DNA microarray, site-directed mutagenesis Journal of virology Medium 26792738
2016 JMJD5 depletion decreases acetylation and detyrosination of α-tubulin (markers of microtubule stability), sensitizing cancer cells to microtubule-destabilizing agents; JMJD5 regulates MAP1B protein levels; MAP1B overexpression rescues microtubule destabilization from JMJD5 depletion. siRNA knockdown, immunofluorescence, nocodazole sensitivity assay, Western blot, rescue overexpression experiments Cell cycle (Georgetown, Tex.) Medium 27715397
2017 JMJD5 and JMJD7 are divalent cation-dependent proteases that preferentially cleave histone tails (H2, H3, H4) containing methylated arginine residues; after initial cleavage they act as aminopeptidases digesting C-terminal products; JMJD5-deficient fibroblasts show dramatically increased levels of methylated arginines and histones, providing a mechanism for removal of arginine-methylated histone tails. In vitro protease assay with histone peptides, mass spectrometry, JMJD5-deficient fibroblasts, immunoblot Proceedings of the National Academy of Sciences of the United States of America High 28847961
2017 JMJD5 is a Cathepsin L-type protease that clips the histone H3 N-tail under DNA damage stress; it cleaves specifically at the carboxyl side of monomethyl-lysine (Kme1) residues; in vitro, JMJD5 cleaves Kme1 H3 peptides but not Kme2, Kme3, or unmethylated peptides; in vivo, K9 of H3.3 is the major cleavage site; cleavage is enriched at JMJD5-bound gene promoters. In vitro H3 peptide digestion, mass spectrometry, ChIP, DNA damage induction, cellular H3 cleavage assays EMBO reports High 28982940
2017 Loss of jmjd-5 in C. elegans results in increased H3K36me2, hypersensitivity to ionizing radiation, meiotic defects, and aberrant retention of RAD-51 at double-strand breaks; genetic interaction studies with rtel-1, rfs-1, and helq-1 indicate jmjd-5 prevents stalled postsynaptic recombination intermediates and favors RAD-51 removal; a catalytically inactive jmjd-5 mutant phenocopies loss, establishing H3K36me2 regulation as required for late steps of homologous recombination. C. elegans knockout, catalytic mutant, genetic epistasis, RAD-51 immunostaining, ionizing radiation sensitivity assays PLoS genetics High 28207814
2017 Miz1 directly represses Kdm8 transcription in Schwann cells; elevated Kdm8 in Miz1ΔPOZ cells causes decreased H3K36me2 at cell-cycle-related gene loci, leading to re-entry of adult Schwann cells into the cell cycle and peripheral neuropathy. RNA sequencing, ChIP, transgenic mouse model (Miz1ΔPOZ), cell cycle analysis The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 29217679
2018 JMJD5 catalyses stereoselective C-3 hydroxylation of arginine residues in peptide sequences from human RCCD1 and ribosomal protein RPS6; high-resolution crystal structures reveal active site and substrate binding features consistent with an arginine hydroxylase rather than a lysine demethylase. Peptide screening, in vitro hydroxylase assay with mass spectrometry, X-ray crystallography Nature communications High 29563586
2018 Crystal structures of JMJD5 with arginine derivatives reveal a Tudor domain-like binding pocket accommodating methylated arginine (not lysine); JMJD5 specifically binds arginine-methylated histone tails but not those with additional lysine acetylation; a glutamine near the catalytic center suggests an imidic acid-mediated catalytic mechanism for proteolysis. X-ray crystallography, biochemical binding assays (fluorescence polarization/SPR), substrate specificity assays Scientific reports High 29459673
2018 KDM8 acts as a dual coactivator of androgen receptor (AR) and PKM2 in prostate cancer: direct interaction with AR elevates androgen-response genes (including ANCCA/ATAD2 and EZH2) under androgen-deprived conditions; direct interaction with PKM2 in the cytosol promotes PKM2 nuclear translocation and HIF-1α coactivation of glycolytic genes; shRNA knockdown validates both functions. Co-immunoprecipitation, shRNA knockdown, ChIP, gene expression analysis, metabolic assays Oncogene Medium 30072740
2018 JMJD5 interacts with CRY1 in an FBXL3-dependent manner and facilitates targeting of CRY1 to the proteasome; genetic deletion of JMJD5 results in greater CRY1 stability, reduced CRY1-proteasome association, and disrupted circadian gene expression; JMJD5 is required for AMPK-induced CRY1 degradation; JMJD5 cooperates with CRY1 to repress CLOCK-BMAL1. Co-immunoprecipitation, genetic knockout, proteasome association assay, luciferase circadian reporter assay, AMPK degradation assay PLoS biology High 30500822
2020 JMJD5 knockout leads to nucleosome accumulation at position +1 from transcription start sites and loss of transcription of many genes; CDK9-mediated phosphorylation of Pol II CTD at HR-Ser2p(1,2)-Ser5p(2) allows Pol II to bind JMJD5 via its N-terminal domain, bringing JMJD5 near the +1 nucleosome to clip histones and contribute to release of Pol II pausing. JMJD5 knockout, ChIP-seq, Co-immunoprecipitation, RNA-seq, phospho-peptide binding assays Proceedings of the National Academy of Sciences of the United States of America High 32747552
2023 KDM8 maintains an active mitochondrial gene network in cardiomyocytes by demethylating H3K36me2 at the TBX15 locus, repressing Tbx15; Kdm8 deletion increases H3K36me2, activates Tbx15, and represses NAD+ pathway genes before dilated cardiomyopathy initiates; NAD+ supplementation prevents DCM in Kdm8 mutant mice; TBX15 overexpression blunts NAD+-activated cardiomyocyte respiration. Cardiomyocyte-specific knockout mouse, ChIP-seq, RNA-seq, NAD+ supplementation rescue, TBX15 overexpression, echocardiography Nature cardiovascular research High 38665902
2023 JMJD5 cooperates with E3 ligase HUWE1 to destabilize EGFR and TKI-resistant EGFR mutants for proteasomal degradation, inhibiting NSCLC growth; JMJD5 can be transported into recipient cells via extracellular vesicles. Co-immunoprecipitation, proteasome inhibitor experiments, siRNA knockdown, extracellular vesicle isolation, xenograft tumor models Cell death & disease Medium 37813845
2022 HEATR5B-881aa (a protein encoded by circHEATR5B) interacts directly with JMJD5 and reduces its stability by phosphorylating Ser361 of JMJD5; JMJD5 knockdown increases PKM2 enzymatic activity and suppresses glycolysis and proliferation in GBM cells. Mass spectrometry, co-immunoprecipitation, phosphorylation site mapping, siRNA knockdown, glycolysis assays, xenograft model Journal of experimental & clinical cancer research : CR Medium 35538499
2026 KDM8 depletion increases HR while its overexpression reduces HR; a concomitant decrease in NHEJ compensates, an effect partly independent of its demethylase activity and unrelated to cell cycle alterations; FRET experiments in living cells demonstrate a direct interaction between KDM8 and Rad51 after DNA damage. High-throughput screening, HR/NHEJ reporter assays, FRET in living cells, overexpression and knockdown Cell cycle (Georgetown, Tex.) Medium 42001401
2025 JMJD5 hydroxylates an arginine residue on ISY1; hydroxylated ISY1 then binds to and reduces the activity of Protein Arginine N-methyltransferase 6 (PRMT6); inactivation of PRMT6 rescues the majority of the molecular phenotype driven by JMJD5 loss, establishing JMJD5-ISY1-PRMT6 as a principal signalling pathway for JMJD5 enzymatic function. Hydroxylase activity assay, co-immunoprecipitation, PRMT6 activity assay, siRNA knockdown/epistasis, mass spectrometry bioRxivpreprint Medium bio_10.1101_2025.09.27.678987
2025 The JMJD5:RCCD1 protein complex is essential for suppressing replication stress and genome instability; cancer missense mutations disrupt the JMJD5:RCCD1 interaction and impair its hydroxylase activity; the complex interacts with RAD51 paralogues and is required for normal replication fork restart. Structural analysis of cancer mutants, co-immunoprecipitation, replication stress assays (γH2AX, fiber assay), interaction mapping with RAD51 paralogues bioRxivpreprint Medium bio_10.1101_2025.11.22.689938

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. Proceedings of the National Academy of Sciences of the United States of America 264 24344305
2010 KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 157 20457893
2010 Jumonji domain protein JMJD5 functions in both the plant and human circadian systems. Proceedings of the National Academy of Sciences of the United States of America 134 21115819
2018 KDM8/JMJD5 as a dual coactivator of AR and PKM2 integrates AR/EZH2 network and tumor metabolism in CRPC. Oncogene 89 30072740
2012 Jmjd5, an H3K36me2 histone demethylase, modulates embryonic cell proliferation through the regulation of Cdkn1a expression. Development (Cambridge, England) 80 22241836
2012 Histone demethylase JMJD5 is essential for embryonic development. Biochemical and biophysical research communications 64 22402282
2017 Clipping of arginine-methylated histone tails by JMJD5 and JMJD7. Proceedings of the National Academy of Sciences of the United States of America 60 28847961
2012 Crystal structure and functional analysis of JMJD5 indicate an alternate specificity and function. Molecular and cellular biology 59 22851697
2012 JMJD5, a Jumonji C (JmjC) domain-containing protein, negatively regulates osteoclastogenesis by facilitating NFATc1 protein degradation. The Journal of biological chemistry 54 22375008
2022 A novel protein encoded by ZCRB1-induced circHEATR5B suppresses aerobic glycolysis of GBM through phosphorylation of JMJD5. Journal of experimental & clinical cancer research : CR 53 35538499
2017 JMJD5 cleaves monomethylated histone H3 N-tail under DNA damaging stress. EMBO reports 50 28982940
2018 JMJD5 is a human arginyl C-3 hydroxylase. Nature communications 47 29563586
2014 JMJD5 regulates cell cycle and pluripotency in human embryonic stem cells. Stem cells (Dayton, Ohio) 40 24740926
2018 Down-regulation of JMJD5 suppresses metastasis and induces apoptosis in oral squamous cell carcinoma by regulating p53/NF-κB pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 32 30551455
2017 JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity. PLoS genetics 32 28207814
2016 Epigenetic silencing of JMJD5 promotes the proliferation of hepatocellular carcinoma cells by down-regulating the transcription of CDKN1A 686. Oncotarget 30 26760772
2015 JMJD5 interacts with p53 and negatively regulates p53 function in control of cell cycle and proliferation. Biochimica et biophysica acta 30 26025680
2018 Specific Recognition of Arginine Methylated Histone Tails by JMJD5 and JMJD7. Scientific reports 29 29459673
2017 PHD3 is a transcriptional coactivator of HIF-1α in nucleus pulposus cells independent of the PKM2-JMJD5 axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29 28495754
2016 Hepatocyte Factor JMJD5 Regulates Hepatitis B Virus Replication through Interaction with HBx. Journal of virology 29 26792738
2013 Structure of the JmjC-domain-containing protein JMJD5. Acta crystallographica. Section D, Biological crystallography 26 24100311
2015 JMJD5 is a potential oncogene for colon carcinogenesis. International journal of clinical and experimental pathology 23 26261525
2015 JMJD5 (Jumonji Domain-containing 5) Associates with Spindle Microtubules and Is Required for Proper Mitosis. The Journal of biological chemistry 22 26710852
2017 Miz1 Controls Schwann Cell Proliferation via H3K36me2 Demethylase Kdm8 to Prevent Peripheral Nerve Demyelination. The Journal of neuroscience : the official journal of the Society for Neuroscience 20 29217679
2023 KDM8 epigenetically controls cardiac metabolism to prevent initiation of dilated cardiomyopathy. Nature cardiovascular research 17 38665902
2013 Identification and functional implication of nuclear localization signals in the N-terminal domain of JMJD5. Biochimie 17 23948433
2015 Jmjd5 functions as a regulator of p53 signaling during mouse embryogenesis. Cell and tissue research 15 26334721
2020 JMJD5 couples with CDK9 to release the paused RNA polymerase II. Proceedings of the National Academy of Sciences of the United States of America 14 32747552
2021 JMJD5 attenuates oxygen-glucose deprivation and reperfusion-induced injury in cardiomyocytes through regulation of HIF-1α-BNIP3. The Kaohsiung journal of medical sciences 12 34369657
2018 JMJD5 links CRY1 function and proteasomal degradation. PLoS biology 12 30500822
2016 Depletion of JMJD5 sensitizes tumor cells to microtubule-destabilizing agents by altering microtubule stability. Cell cycle (Georgetown, Tex.) 10 27715397
2023 JMJD5 inhibits lung cancer progression by facilitating EGFR proteasomal degradation. Cell death & disease 8 37813845
2022 The Novel Protease Activities of JMJD5-JMJD6-JMJD7 and Arginine Methylation Activities of Arginine Methyltransferases Are Likely Coupled. Biomolecules 7 35327545
2018 Soybean (Glycine max) prevents the progression of breast cancer cells by downregulating the level of histone demethylase JMJD5. Journal of cancer research and therapeutics 7 30249876
2023 Allyl Isothiocyanate Suppresses the Proliferation in Oral Squamous Cell Carcinoma via Mediating the KDM8/CCNA1 Axis. Biomedicines 5 37893043
2022 Structural analysis of the 2-oxoglutarate binding site of the circadian rhythm linked oxygenase JMJD5. Scientific reports 5 36450832
2024 Deciphering KDM8 dysregulation and CpG methylation in hepatocellular carcinoma using multi-omics and machine learning. Epigenomics 4 39072393
2025 METTL14-Mediated M6A Modification of LINC01094 Induces Glucose Metabolic Reprogramming in Breast Cancer by Recruiting the PKM2/JMJD5 Complex. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 3 40470773
2023 JMJD5 inhibits lung cancer progression by regulating glucose metabolism through the p53/TIGAR pathway. Medical oncology (Northwood, London, England) 3 37043051
2022 Elevated Expression of JMJD5 Protein Due to Decreased miR-3656 Levels Contributes to Cancer Stem Cell-Like Phenotypes under Overexpression of Cancer Upregulated Gene 2. Biomolecules 2 35053270
2026 Control of DNA double-strand break repair by the KDM8 histone demethylase. Cell cycle (Georgetown, Tex.) 0 42001401
2026 KDM8/c-Myc axis-mediated glucose metabolism reprogramming promotes the progression of ovarian cancer. Scientific reports 0 42045432
2026 JMJD5: a multifunctional regulator in development, homeostasis, and cancer. Frontiers in cell and developmental biology 0 42238895

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