Affinage

SETMAR

Histone-lysine N-methyltransferase SETMAR · UniProt Q53H47

Length
684 aa
Mass
78.0 kDa
Annotated
2026-06-10
45 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SETMAR (Metnase) is a primate-specific chimeric enzyme that joins a SET lysine methyltransferase domain to a domesticated Hsmar1 transposase domain, and it functions principally in genome maintenance pathways—non-homologous end-joining, replication fork restart, and chromosome decatenation—alongside a transposase-guided role in transcriptional and splicing regulation (PMID:16332963, PMID:35378129). The transposase domain retains ancestral biochemistry: it binds Hsmar1 inverted-repeat (TIR) DNA site-specifically through an R432-containing helix-turn-helix and cleaves DNA via a DDE/DDN-like active site (D483, N610), but a 3'-end cleavage defect prevents full transposition (PMID:17130240, PMID:17877369, PMID:24573677). Crystal structures establish that the catalytic domain forms an F460-mediated dimer required for DNA cleavage and binding, and that each DNA-binding domain contacts TIR DNA through an extensive hydrogen-bond network (PMID:20521842, PMID:35378129). In DNA repair, SETMAR interacts with DNA Ligase IV and with hPso4/PRP19—which recruits it to double-strand breaks after ionizing radiation—to promote accurate NHEJ and suppress chromosomal translocations (PMID:18263876, PMID:18773976, PMID:20620605), while its ssDNA-preferring endonuclease activity (D483-dependent) processes overhangs to stimulate end joining (PMID:21491884, PMID:24573677). SETMAR promotes restart of stalled replication forks, binding PCNA and RAD9 and loading Exonuclease 1 onto ssDNA overhangs to drive 5' resection (PMID:20457750, PMID:27974460). It physically stimulates Topoisomerase IIα decatenation and the decatenation checkpoint, an activity repressed by SETMAR automethylation at K485 (PMID:18790802, PMID:19390626, PMID:19458360). Chk1 phosphorylation at Ser495 acts as a switch that promotes chromatin association and H3K36 methylation at DSBs while inhibiting fork restart, and phosphorylated SETMAR reciprocally stabilizes Chk1 (PMID:22231448, PMID:25024738). Its SET activity deposits H3K36me2 to euchromatinize chromatin and recruit Ku-dependent NHEJ factors to breaks, and it also methylates the non-histone splicing factor snRNP70 at K130 (PMID:25795785, PMID:32458986). Genome-wide, the transposase domain targets the methylase to thousands of Hsmar1 TIR remnants to regulate gene expression and alternative splicing, and SETMAR pre-mRNA is itself alternatively spliced by NONO/SFPQ to generate isoforms with distinct chromatin and repair functions (PMID:30329085, PMID:32950106, PMID:35378129, PMID:41535889).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2005 High

    Established the founding dual identity of SETMAR by showing a single protein both methylates histone H3 and functions in DSB repair and DNA integration, defining it as a chimeric chromatin/repair enzyme.

    Evidence In vitro methyltransferase assay, ionizing radiation resistance and plasmid integration assays in human cells

    PMID:16332963

    Open questions at the time
    • Did not resolve which domain contributes to each activity
    • Histone substrate specificity later contested for nucleosomal H3K36
  2. 2006 High

    Determined that the transposase domain retains ancestral Hsmar1 activities—TIR binding, paired-end complex assembly, and 5' cleavage—but is defective in 3' cleavage, explaining why SETMAR no longer transposes yet keeps DNA-acting chemistry.

    Evidence In vitro transposition, DNA binding, paired-end complex, and cleavage assays with isolated and full-length protein

    PMID:17130240

    Open questions at the time
    • Did not connect residual transposase activity to a cellular repair role
    • In vivo genomic targeting not yet mapped
  3. 2007 High

    Mapped the separable molecular determinants of the transposase domain, assigning TIR-specific binding to HTH residue R432 and cleavage to DDE residue D483, and showing binding and cleavage are uncoupled.

    Evidence Site-directed mutagenesis with in vitro binding and cleavage assays; in vivo repair pathway analysis

    PMID:17403897 PMID:17877369

    Open questions at the time
    • Functional consequence of uncoupled cleavage in cells unclear
    • Repair pathway choice at SETMAR-induced nicks not mechanistically dissected
  4. 2008 High

    Defined how SETMAR is recruited to and acts at DSBs by identifying physical partners—hPso4/PRP19 (required for DSB localization and end joining) and DNA Ligase IV (for accurate NHEJ)—and a parallel Topo IIα decatenation function regulated by K485 automethylation.

    Evidence Co-IP, immunofluorescence co-localization, siRNA knockdown, end-joining and decatenation assays with purified proteins

    PMID:18263876 PMID:18773976 PMID:18790802

    Open questions at the time
    • Order of recruitment relative to other NHEJ factors unresolved
    • Whether automethylation is dynamically regulated in cells not shown
  5. 2009 High

    Confirmed the decatenation function in disease-relevant contexts by showing SETMAR controls the mitotic decatenation checkpoint and confers resistance to Topo IIα inhibitors in cancer cells.

    Evidence Co-IP, siRNA knockdown, metaphase/mitotic checkpoint assays, and in vitro decatenation assays with VP-16 and adriamycin

    PMID:19390626 PMID:19458360

    Open questions at the time
    • Direct structural basis of Topo IIα stimulation not defined
    • Did not establish whether methyltransferase activity contributes
  6. 2010 High

    Extended SETMAR's roles to replication-fork restart and translocation suppression and provided the first crystal structure, showing F460-mediated dimerization is required for cleavage, DNA binding, and NHEJ.

    Evidence DNA fiber fork-restart assays, Co-IP with PCNA/RAD9 and murine Lig IV, X-ray crystallography with F460K dimerization mutant

    PMID:20416268 PMID:20457750 PMID:20521842 PMID:20620605

    Open questions at the time
    • Structure covered only the transposase catalytic domain, not full-length or SET domain
    • How hPso4 switches SETMAR from TIR to DSB sites only inferred from in vitro binding
  7. 2011 High

    Established that SETMAR's ssDNA-preferring endonuclease activity is functionally required for NHEJ, linking the transposase-derived nuclease to end processing.

    Evidence In vitro endonuclease assay and cell-extract end-joining complementation with wild-type versus D483A SETMAR

    PMID:21491884

    Open questions at the time
    • Physiological overhang substrates in cells not directly identified
    • Coordination with other end-processing nucleases unresolved
  8. 2012 High

    Identified Chk1 phosphorylation of Ser495 as a regulatory switch that partitions SETMAR between DSB repair (promoted) and fork restart (inhibited), explaining how one protein serves opposing repair contexts.

    Evidence In vivo phospho-site mapping, Chk1 kinase assay, S495A mutant chromatin-association, DSB repair and fork-restart assays

    PMID:22231448

    Open questions at the time
    • Upstream signals selecting between the two outputs not defined
    • Phosphatase reversing S495 unknown
  9. 2013 High

    Clarified the limits of SETMAR's nuclease in physiological end joining by comparing it directly to Artemis, showing SETMAR cleaves overhangs but, unlike Artemis, does not stimulate joining of 3'-phosphoglycolate ends in cell extracts.

    Evidence In vitro endonuclease assays with modified DSB substrates and cell-extract end-joining assays

    PMID:23602515

    Open questions at the time
    • Distinct in vivo substrate niche of SETMAR versus Artemis not pinned down
    • Effect of base damage on cellular repair outcome untested
  10. 2014 High

    Refined the catalytic and DNA-recognition architecture by showing the unique DDN motif (N610) and ssDNA-binding catalytic domain are required for NHEJ and fork restart, while a SETMAR–DDB1 axis feeds back to stabilize Chk1.

    Evidence DDN→DDD/DDE mutagenesis with in vivo and in vitro functional readouts; Co-IP and ubiquitination/half-life assays for Chk1 stabilization

    PMID:24573677 PMID:25024738

    Open questions at the time
    • Chk1-stabilization feedback shown in a single study without reciprocal validation
    • How HTH-dsDNA and catalytic-ssDNA binding are coordinated on a single substrate unclear
  11. 2015 High

    Reassigned key biochemical activities by identifying snRNP70 K130 as a non-histone substrate (and reporting SETMAR is inactive on nucleosomal H3K36 in vitro), while assigning a methyltransferase-independent ssDNA-cleavage role to the SET domain in fork recovery.

    Evidence Quantitative methyl-proteomics and in vitro/in-cell methylation assays; SET-domain deletion with fork-restart and overhang-cleavage assays

    PMID:25795785 PMID:26437079

    Open questions at the time
    • Apparent conflict between in vitro nucleosome inactivity and cellular H3K36me2 roles unresolved
    • Functional consequence of snRNP70 K130 methylation for splicing not demonstrated
  12. 2016 Medium

    Connected SETMAR's DNA-binding activity to resection machinery by showing it associates with Exo1 and loads it onto ssDNA overhangs to drive 5' resection at stalled forks, independent of its cleavage activity.

    Evidence Co-IP, in vitro ssDNA-overhang loading assay, and Exo1 exonuclease assays with cleavage-dead and DNA-binding SETMAR mutants

    PMID:27974460

    Open questions at the time
    • Single-lab in vitro loading assay without orthogonal cellular validation
    • Stoichiometry of the SETMAR–Exo1–ssDNA complex undefined
  13. 2019 Medium

    Demonstrated a genome-regulatory role distinct from repair by showing the DNA-binding domain targets the methylase to thousands of Hsmar1 TIR remnants and that methylase activity is required to activate ~1500 genes.

    Evidence Wild-type versus methylase-deficient overexpression with RNA-seq and prior ChIP localization

    PMID:30329085

    Open questions at the time
    • Overexpression-based, single lab, not validated by knockout at this stage
    • Direct versus indirect transcriptional effects not distinguished
  14. 2022 High

    Provided the high-resolution structural and genome-wide basis for TIR targeting, showing a dimeric SETMAR contacting TIR DNA through 32 hydrogen bonds and binding ~5000 TIR sites, with knockout altering shared gene-expression and splicing programs.

    Evidence 2.37 Å X-ray crystallography, ChIP-seq, and SETMAR KO RNA-seq in two cell lines

    PMID:35378129

    Open questions at the time
    • Mechanism linking TIR binding to splicing changes not resolved
    • Causal chromatin marks at regulated loci not mapped
  15. 2020 Medium

    Linked SETMAR-deposited H3K36me2 to NHEJ-factor recruitment and to its own isoform regulation, showing H3K36me2-dependent Ku recruitment, senescence upon knockdown, EEPD1-independent fork cleavage, and NONO/SFPQ control of SETMAR splicing in metastasis.

    Evidence Conditional knockdown, H3K36A histone mutant, Ku80 ChIP/foci, CRISPR KO fork-cleavage epistasis, RNA-IP and metastasis rescue assays

    PMID:32458986 PMID:32743552 PMID:32950106

    Open questions at the time
    • H3K36me2 role contrasts with in vitro nucleosome inactivity (25795785)
    • Isoform-specific functions characterized in single-lab contexts
  16. 2024 Medium

    Embedded SETMAR in a tissue-specific transcriptional cascade and an upstream RNA-modification circuit, showing it methylates H3K36 at the SMARCA2 promoter to drive thyroid differentiation factors, with METTL3/IGF2BP3 m6A controlling SETMAR mRNA.

    Evidence ChIP, ATAC-seq, SMARCA2-enhancer Co-IP, m6A MeRIP and IGF2BP3 RIP with knockdown/overexpression

    PMID:38900084

    Open questions at the time
    • Single-lab, context-restricted to thyroid cells
    • Direct enzymatic deposition versus recruitment of other writers not fully separated
  17. 2026 Medium

    Showed that upstream O-GlcNAcylation of NONO governs SETMAR isoform choice and downstream NHEJ, linking a post-translational signal on a splicing regulator to H3K36me2 and Ku recruitment at DSBs.

    Evidence NONO Ser147Ala mutagenesis, RNA-IP, NONO-SFPQ Co-IP, H3K36me2 ChIP, Ku70 foci, and radiation sensitivity in vitro and in vivo

    PMID:41535889

    Open questions at the time
    • Single-lab study of an upstream regulator rather than SETMAR directly
    • Isoform-specific catalytic differences underlying H3K36me2 suppression not biochemically defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how SETMAR reconciles its reported nucleosomal H3K36me2 deposition in cells with in vitro inactivity on nucleosomes, and how its overlapping repair, decatenation, and transcriptional functions are coordinated within a single protein.
  • No unified biochemical reconstitution of nucleosomal methylation
  • Cofactors or accessory factors enabling H3K36me2 in cells unidentified
  • Quantitative partitioning between repair and transcriptional roles unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 5 GO:0003677 DNA binding 4 GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-73894 DNA Repair 4 R-HSA-4839726 Chromatin organization 3 R-HSA-69306 DNA Replication 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953854 Metabolism of RNA 3
Partners
DDB1EXO1LIG4PCNAPRPF19RAD9ASNRNP70TOP2A

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 SETMAR (Metnase) methylates histone H3 at lysines 4 and 36, promotes non-homologous end-joining (NHEJ) repair of DNA double-strand breaks, and enhances integration of exogenous DNA into host cell genomes. In vitro methyltransferase assay, ionizing radiation resistance assay, plasmid integration assay in human cells Proceedings of the National Academy of Sciences of the United States of America High 16332963
2006 The transposase domain of SETMAR retains ancestral Hsmar1 transposase activities including site-specific DNA binding to transposon inverted repeat (TIR) ends, assembly of a paired-ends complex, cleavage of the 5' end of the TIR element in Mn2+, and integration at TA dinucleotide target sites; however, it has a severe defect in 3'-end cleavage limiting full transposition. In vitro transposition assay, DNA binding assay, paired-end complex assembly, cleavage assay with isolated transposase domain and full-length protein Molecular and cellular biology High 17130240
2007 SETMAR binds Hsmar1 inverted-repeat sequences in vitro and introduces single-strand nicks into them; DNA repair following SETMAR cleavage predominantly follows a homology-dependent pathway rather than NHEJ. In vitro DNA binding assay, nicking assay, in vivo repair pathway analysis using Hsmar1-Ra transposase system Molecular and cellular biology High 17403897
2007 Residue R432 within the helix-turn-helix (HTH) motif is critical for TIR-specific DNA binding (R432A abolishes TIR binding), while the DDE-like motif residue D483 is essential for DNA cleavage activity (D483A abolishes cleavage); importantly, DNA cleavage activity is not coupled to TIR-specific binding. Site-directed mutagenesis, in vitro DNA binding assay, in vitro DNA cleavage assay Biochemistry High 17877369
2008 SETMAR (Metnase) physically interacts with human Pso4 (hPso4/PRP19) forming a stable complex on both TIR and non-TIR DNA; hPso4 is required for Metnase localization to DSB sites after ionizing radiation and for Metnase-mediated stimulation of DNA end joining. Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, DNA end-joining assay The Journal of biological chemistry High 18263876
2008 SETMAR physically interacts and co-localizes with Topoisomerase IIα (Topo IIα), enhances its decatenation of kinetoplast DNA to relaxed circular forms, promotes progression through the decatenation checkpoint, and increases resistance to Topo IIα inhibitors; this enhancement is repressed by SETMAR automethylation at K485. Co-immunoprecipitation, co-localization, in vitro kDNA decatenation assay with purified proteins, nuclear extract decatenation assay with neutralizing antisera, automethylation assay with methyl donor inhibition Nucleic acids research High 18790802
2008 SETMAR interacts with DNA Ligase IV (a core NHEJ component), assists in joining all types of free DNA ends equally, prevents long deletions during NHEJ end processing, and improves NHEJ accuracy; it has little effect on homologous recombination repair. Co-immunoprecipitation, in vivo NHEJ repair assay, γ-H2AX kinetics after ionizing radiation, HR repair assay DNA repair High 18773976
2009 SETMAR interacts with Topo IIα in breast cancer cells; reducing SETMAR expression increases metaphase decatenation checkpoint arrest, sensitizes cells to Topo IIα inhibitors, and directly blocks inhibitory effect of adriamycin on Topo IIα decatenation in vitro. Co-immunoprecipitation, siRNA knockdown, metaphase arrest assay, in vitro decatenation assay PloS one High 19390626
2009 SETMAR regulates the mitotic decatenation checkpoint in acute myeloid leukemia cells; purified SETMAR prevents VP-16 inhibition of Topo IIα decatenation of tangled DNA in vitro. siRNA knockdown, mitotic decatenation checkpoint assay, in vitro kDNA decatenation assay with purified proteins and VP-16 Blood High 19458360
2010 SETMAR promotes restart of stalled replication forks; its knockdown sensitizes cells to replication stress and confers a marked defect in fork restart; SETMAR co-immunoprecipitates with PCNA and RAD9 (member of the RAD9-HUS1-RAD1 checkpoint complex); SETMAR also promotes Topo IIα-mediated relaxation of positively supercoiled DNA. siRNA knockdown, replication fork restart assay (DNA fiber analysis), γ-H2AX resolution assay, co-immunoprecipitation with PCNA and RAD9, supercoiled DNA relaxation assay Nucleic acids research High 20457750
2010 The crystal structure of the SETMAR transposase catalytic domain reveals a dimeric enzyme with unusual active site plasticity; the dimeric form (mediated by F460) is required for DNA cleavage, DNA-binding, and NHEJ activities, as shown by a dimerization mutant F460K. X-ray crystallography (two crystal structures), dimerization mutant F460K functional characterization, DNA cleavage assay, DNA-binding assay, NHEJ assay Biochemistry High 20521842
2010 SETMAR suppresses chromosomal translocations in murine cells; it interacts with murine Lig IV and enhances NHEJ in murine cells, demonstrating integration into the pre-existing NHEJ pathway after primate-specific emergence. Chromosomal translocation assay in murine cells, co-immunoprecipitation with murine Lig IV, NHEJ assay Cancer genetics and cytogenetics Medium 20620605
2010 hPso4, once it forms a complex with SETMAR, negatively regulates SETMAR's TIR DNA-binding activity; in the SETMAR-hPso4-DNA complex, hPso4 is solely responsible for DNA binding, suggesting hPso4 switches SETMAR from TIR sites to non-TIR DSB sites. Electrophoretic mobility shift assay (EMSA), stoichiometric analysis of protein-DNA complexes, competitive binding with TIR and non-TIR DNA Archives of biochemistry and biophysics Medium 20416268
2011 SETMAR possesses a unique endonuclease activity that preferentially acts on ssDNA and ssDNA-overhang of partial duplex DNA; the D483A endonuclease-dead mutant fails to stimulate DNA end joining in cell extracts, establishing the nuclease activity as required for NHEJ. In vitro endonuclease assay, cell extract complementation assay with wt and D483A mutant SETMAR, DNA end-joining assay Biochemistry High 21491884
2012 Chk1 phosphorylates SETMAR specifically at Ser495 in vivo in response to ionizing radiation; S495 phosphorylation promotes SETMAR chromatin association at DSBs and H3K36 methylation near DSBs, enhancing DSB repair; conversely, the S495A mutant shows increased restart of stalled replication forks, demonstrating that phosphorylation differentially regulates these two SETMAR functions. In vivo phosphorylation assay (mass spectrometry and phospho-specific antibody), Chk1 kinase assay, S495A mutant chromatin association assay, DSB repair assay, replication fork restart assay Oncogene High 22231448
2013 Both SETMAR and Artemis endonucleases trim 3' overhangs of duplex DNA double-strand break substrates including those bearing 3'-phosphoglycolates; SETMAR cleaves more evenly across the overhang with sequence dependence; thymine glycol in a 3' overhang severely inhibits SETMAR cleavage near the modified base; in cell extract end-joining assays, Artemis (but not SETMAR) robustly stimulates end joining of 3'-PG overhangs. In vitro endonuclease assay with defined DSB substrates bearing various modifications, human cell extract end-joining assay DNA repair High 23602515
2014 The unique DDN catalytic motif (N610) of the SETMAR transposase domain is required for its in vivo NHEJ repair and replication fork restart functions; substitution to DDD or DDE reduces ssDNA-overhang cleavage activity and ssDNA binding by the catalytic domain. The helix-turn-helix domain binds dsDNA while the catalytic domain binds ssDNA. Site-directed mutagenesis (DDN→DDD, DDN→DDE), in vivo NHEJ assay, replication fork restart assay, in vitro ssDNA cleavage assay, DNA binding assay The Journal of biological chemistry High 24573677
2014 Phosphorylated SETMAR feeds back to increase Chk1 stability by decreasing Chk1 interaction with DDB1 and reducing Chk1 ubiquitination, thereby preventing Cul4A-mediated Chk1 degradation. Co-immunoprecipitation (SETMAR-DDB1 interaction), ubiquitination assay, Chk1 half-life measurement Cell division Medium 25024738
2015 SETMAR methylates lysine 130 of the mRNA splicing factor snRNP70 in vitro and in cells, primarily generating monomethylation; this identifies snRNP70 as a non-histone substrate of SETMAR and suggests SETMAR may regulate splicing through this modification. SETMAR does not methylate H3K36 in vitro and is not active on nucleosomes. Quantitative proteomic analysis of methylated lysine, in vitro methyltransferase assay with snRNP70, mass spectrometry verification in cells, negative result for H3K36 methylation in vitro The Journal of biological chemistry High 25795785
2015 The SET domain of SETMAR is necessary for recovery from replication fork damage (hydroxyurea treatment) and for 5'-end ssDNA-overhang cleavage at fork and non-fork DNA substrates; this cleavage function of the SET domain does not require H3K36me2 activity. SET domain deletion mutant, replication fork restart assay (DNA fiber analysis), in vitro ssDNA-overhang cleavage assay PloS one Medium 26437079
2016 SETMAR associates with Exonuclease 1 (Exo1) and mediates loading of Exo1 onto ssDNA overhangs at stalled replication forks; SETMAR enhances Exo1-mediated 5'-end resection on lagging strand DNA through its DNA-binding activity (not its cleavage activity). Co-immunoprecipitation of SETMAR and Exo1, in vitro ssDNA overhang loading assay, Exo1 exonuclease assay with SETMAR cleavage-dead and DNA-binding mutants The Journal of biological chemistry Medium 27974460
2019 The DNA-binding domain of SETMAR targets the enzyme to transposon-end remnants (Hsmar1 TIR sequences) in human chromatin; modest SETMAR overexpression changes expression of ~1500 genes dependent on methylase activity; methylase-deficient SETMAR changes far fewer genes mostly downward, indicating the methylase is required for gene activation. Overexpression of wild-type and methylase-deficient SETMAR in human cells, transcriptome analysis (RNA-seq), chromatin binding established by prior ChIP data cited Nucleic acids research Medium 30329085
2020 NONO regulates the alternative splicing of SETMAR pre-mRNA (exon skipping) by binding its motif primarily through the RRM2 domain, in conjunction with its interaction partner SFPQ; SETMAR-L (long) isoform reverses NONO-knockdown-mediated metastasis, with SETMAR-L inducing H3K27me3 at promoters of metastatic oncogenes to suppress their transcription. NONO knockdown/overexpression, SETMAR-L rescue experiments, RNA-IP (NONO binding to SETMAR pre-mRNA), Co-IP (NONO-SFPQ), in vitro/in vivo metastasis assays, H3K27me3 ChIP Molecular therapy : the journal of the American Society of Gene Therapy Medium 32950106
2020 In glioblastoma radiation-resistant residual cells, SETMAR upregulation mediates high levels of H3K36me2, causing global euchromatization; elevated H3K36me2 is required for efficient recruitment of NHEJ proteins (Ku80) to double-strand breaks; conditional SETMAR knockdown induces irreversible senescence; H3K36A mutant cells cannot retain Ku80 at DSBs, impairing NHEJ. SETMAR conditional knockdown, H3K36A histone mutant expression, γ-H2AX and Ku80 ChIP/foci assays, senescence assay, orthotopic mouse model Neuro-oncology Medium 32458986
2020 CRISPR/Cas9 knockout of Metnase results in stalled replication forks being cleaved normally (EEPD1-dependent), indicating Metnase nuclease is not required for initial fork cleavage; Metnase KO cells show H3K36me2 reduction at stalled forks, suggesting Metnase promotes DDR factor recruitment via H3K36me2; Metnase and EEPD1 show epistasis in response to etoposide. CRISPR/Cas9 knockout, replication fork cleavage assay, H3K36me2 ChIP at stalled forks, etoposide sensitivity (double knockout epistasis) NAR cancer Medium 32743552
2022 Crystal structure at 2.37 Å reveals SETMAR forms a dimeric complex with each DNA-binding domain bound specifically to TIR DNA through 32 hydrogen bonds; SETMAR recognizes primarily ~5000 TIR sequences genome-wide (ChIP-seq); SETMAR KO identifies 163 shared differentially expressed genes and 233 shared alternative splicing events including splicing factors and neuronal genes. X-ray crystallography (2.37 Å), ChIP-seq, SETMAR KO transcriptomics (RNA-seq) in two cell lines The Journal of biological chemistry High 35378129
2024 SETMAR methylates dimethylated H3K36 at the SMARCA2 promoter to promote SMARCA2 transcription; SMARCA2 then binds enhancers of thyroid differentiation transcription factors PAX8 and FOXE1 to promote their expression by enhancing chromatin accessibility; additionally, METTL3-mediated m6A methylation of SETMAR mRNA regulates SETMAR expression in an IGF2BP3-dependent manner. ChIP assay (SETMAR at SMARCA2 promoter), ATAC-seq (chromatin accessibility), SMARCA2-enhancer Co-IP, SETMAR KD/OE, m6A MeRIP assay, IGF2BP3 RIP Advanced science Medium 38900084
2026 O-GlcNAcylation of NONO at Ser147 stabilizes NONO interaction with SFPQ and regulates alternative splicing of SETMAR pre-mRNA; loss of this modification impairs NONO binding to SETMAR pre-mRNA, increasing production of the truncated SETMAR-S isoform; SETMAR-S suppresses H3K36me2 generation and impairs Ku70 recruitment to DSBs, compromising NHEJ repair. O-GlcNAc site mutagenesis (Ser147Ala), RNA-IP (NONO binding to SETMAR pre-mRNA), Co-IP (NONO-SFPQ), H3K36me2 ChIP, Ku70 foci assay at DSBs, ionizing radiation sensitivity in vitro and in vivo Genome biology Medium 41535889

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The SET domain protein Metnase mediates foreign DNA integration and links integration to nonhomologous end-joining repair. Proceedings of the National Academy of Sciences of the United States of America 123 16332963
2007 The ancient mariner sails again: transposition of the human Hsmar1 element by a reconstructed transposase and activities of the SETMAR protein on transposon ends. Molecular and cellular biology 94 17403897
2006 The human SETMAR protein preserves most of the activities of the ancestral Hsmar1 transposase. Molecular and cellular biology 83 17130240
2020 NONO Inhibits Lymphatic Metastasis of Bladder Cancer via Alternative Splicing of SETMAR. Molecular therapy : the journal of the American Society of Gene Therapy 70 32950106
2008 Human Pso4 is a metnase (SETMAR)-binding partner that regulates metnase function in DNA repair. The Journal of biological chemistry 68 18263876
2009 Metnase mediates chromosome decatenation in acute leukemia cells. Blood 52 19458360
2010 Metnase promotes restart and repair of stalled and collapsed replication forks. Nucleic acids research 51 20457750
2008 The SET and transposase domain protein Metnase enhances chromosome decatenation: regulation by automethylation. Nucleic acids research 51 18790802
2010 Metnase/SETMAR: a domesticated primate transposase that enhances DNA repair, replication, and decatenation. Genetica 44 20309721
2009 Metnase mediates resistance to topoisomerase II inhibitors in breast cancer cells. PloS one 44 19390626
2011 Biochemical characterization of metnase's endonuclease activity and its role in NHEJ repair. Biochemistry 43 21491884
2008 The human set and transposase domain protein Metnase interacts with DNA Ligase IV and enhances the efficiency and accuracy of non-homologous end-joining. DNA repair 40 18773976
2007 Biochemical characterization of a SET and transposase fusion protein, Metnase: its DNA binding and DNA cleavage activity. Biochemistry 40 17877369
2012 Chk1 phosphorylation of Metnase enhances DNA repair but inhibits replication fork restart. Oncogene 33 22231448
2020 Inhibition of SETMAR-H3K36me2-NHEJ repair axis in residual disease cells prevents glioblastoma recurrence. Neuro-oncology 31 32458986
2015 A Proteomic Strategy Identifies Lysine Methylation of Splicing Factor snRNP70 by the SETMAR Enzyme. The Journal of biological chemistry 30 25795785
2012 Targeting the transposase domain of the DNA repair component Metnase to enhance chemotherapy. Cancer research 30 23090115
2014 The DDN catalytic motif is required for Metnase functions in non-homologous end joining (NHEJ) repair and replication restart. The Journal of biological chemistry 28 24573677
2010 The transposase domain protein Metnase/SETMAR suppresses chromosomal translocations. Cancer genetics and cytogenetics 26 20620605
2019 Human SETMAR is a DNA sequence-specific histone-methylase with a broad effect on the transcriptome. Nucleic acids research 24 30329085
2010 Crystal structure of the human Hsmar1-derived transposase domain in the DNA repair enzyme Metnase. Biochemistry 23 20521842
2013 Trimming of damaged 3' overhangs of DNA double-strand breaks by the Metnase and Artemis endonucleases. DNA repair 20 23602515
2013 Study of the interaction among Notch pathway receptors, correlation with stemness, as well as their interaction with CD44, dipeptidyl peptidase-IV, hepatocyte growth factor receptor and the SETMAR transferase, in colon cancer stem cells. Journal of receptor and signal transduction research 20 23964856
2024 SETMAR Facilitates the Differentiation of Thyroid Cancer by Regulating SMARCA2-Mediated Chromatin Remodeling. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 38900084
2021 Structure, Activity, and Function of SETMAR Protein Lysine Methyltransferase. Life (Basel, Switzerland) 15 34947873
2017 SETMAR isoforms in glioblastoma: A matter of protein stability. Oncotarget 15 28038463
2016 Metnase Mediates Loading of Exonuclease 1 onto Single Strand Overhang DNA for End Resection at Stalled Replication Forks. The Journal of biological chemistry 15 27974460
2022 Metnase and EEPD1: DNA Repair Functions and Potential Targets in Cancer Therapy. Frontiers in oncology 14 35155245
2015 The SET Domain Is Essential for Metnase Functions in Replication Restart and the 5' End of SS-Overhang Cleavage. PloS one 14 26437079
2010 Regulation of Metnase's TIR binding activity by its binding partner, Pso4. Archives of biochemistry and biophysics 14 20416268
2019 The roles of the human SETMAR (Metnase) protein in illegitimate DNA recombination and non-homologous end joining repair. DNA repair 13 31238295
2011 Neoamphimedine circumvents metnase-enhanced DNA topoisomerase IIα activity through ATP-competitive inhibition. Marine drugs 13 22163192
2020 Distinct roles of structure-specific endonucleases EEPD1 and Metnase in replication stress responses. NAR cancer 12 32743552
2014 The DNA repair component Metnase regulates Chk1 stability. Cell division 11 25024738
2014 Potential role for the Metnase transposase fusion gene in colon cancer through the regulation of key genes. PloS one 11 25333365
2021 Mutation and expression alterations of histone methylation-related NSD2, KDM2B and SETMAR genes in colon cancers. Pathology, research and practice 10 33621919
2022 SETMAR, a case of primate co-opted genes: towards new perspectives. Mobile DNA 8 35395947
2021 Two repeated motifs enriched within some enhancers and origins of replication are bound by SETMAR isoforms in human colon cells. Genomics 8 33812898
2022 Structural and genome-wide analyses suggest that transposon-derived protein SETMAR alters transcription and splicing. The Journal of biological chemistry 7 35378129
2014 Fidelity of end joining in mammalian episomes and the impact of Metnase on joint processing. BMC molecular biology 7 24655462
2021 Genome-wide mapping of binding sites of the transposase-derived SETMAR protein in the human genome. Computational and structural biotechnology journal 6 34377368
2016 Crystallization of and selenomethionine phasing strategy for a SETMAR-DNA complex. Acta crystallographica. Section F, Structural biology communications 3 27599863
2026 O-GlcNAcylation of NONO mediates alternative splicing of SETMAR and facilitates NHEJ repair. Genome biology 1 41535889
2025 A 300 bp non-coding repeat sequence has co-evolved with the ced-2/CRKII-set-23/SETMAR genes of nematodes. microPublication biology 0 41200240
2023 Investigating the Expression Pattern of the SETMAR Gene Transcript Variants in Childhood Acute Leukemia: Revisiting an Old Gene. Journal of pediatric hematology/oncology 0 36706314

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