Affinage

MUS81

Structure-specific endonuclease subunit MUS81 · UniProt Q96NY9

Length
551 aa
Mass
61.2 kDa
Annotated
2026-04-29
100 papers in source corpus 46 papers cited in narrative 46 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MUS81 is the catalytic subunit of two structure-selective endonuclease complexes—MUS81-EME1 and MUS81-EME2—that cleave branched DNA intermediates arising during replication stress and recombination, thereby maintaining genome stability. Both complexes require heterodimerization for nuclease activity and preferentially cleave 3′-flaps, replication fork structures, nicked Holliday junctions, and D-loops via a nick-and-counternick mechanism, with MUS81-EME2 being more active and specialized for S-phase fork restart and ALT telomere maintenance, while MUS81-EME1 partners with SLX1-SLX4 in a G2/M-activated holoenzyme that resolves late recombination intermediates and processes under-replicated DNA at common fragile sites to ensure faithful chromosome segregation (PMID:11719193, PMID:24813886, PMID:24076221, PMID:23811685). Temporal restriction of MUS81 activity is enforced by CDK1-, Polo-like kinase (Cdc5)-, and DDK-dependent phosphorylation of the non-catalytic EME1/Mms4 subunit, which activates nuclease function only after bulk DNA synthesis, while checkpoint kinases Chk1 and Cds1 prevent premature fork cleavage by promoting MUS81 dissociation from chromatin during S phase (PMID:22730299, PMID:28096179, PMID:15805465, PMID:21858151). MUS81 activity is further stimulated by BLM and RECQ5 helicases that displace inhibitory RAD51 filaments from substrates, by Rad54 through direct protein-protein interaction, and is recruited to stalled forks via EZH2-mediated H3K27me3 deposition (PMID:15805243, PMID:28575661, PMID:19017809, PMID:29035360).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Identification of MUS81 as an XPF-family endonuclease subunit linked to recombinational repair of replication damage established the gene's entry into the DNA repair field and defined its checkpoint kinase interaction.

    Evidence Two-hybrid screen with Rad54, co-IP, genetic sensitivity profiling in S. cerevisiae and S. pombe

    PMID:10905349 PMID:11073977

    Open questions at the time
    • Enzymatic activity not yet demonstrated
    • Partner subunit not yet identified
    • Human ortholog not characterized
  2. 2001 High

    Reconstitution of Mus81-Eme1 (fission yeast) and Mus81-Mms4 (budding yeast) as heterodimeric endonucleases established that both subunits are required for activity and that the complex cleaves Holliday junctions and branched DNA structures, defining MUS81 as a structure-selective nuclease.

    Evidence Biochemical purification, in vitro cleavage assays with oligonucleotide substrates, genetic rescue with bacterial RusA in S. pombe; co-IP and substrate comparison in S. cerevisiae; human Mus81 HJ cleavage

    PMID:11641278 PMID:11719193 PMID:11741546

    Open questions at the time
    • Relative preference for HJs vs replication forks unclear
    • Human heterodimer partner not yet identified
  3. 2003 High

    Detailed substrate specificity studies revealed that MUS81 complexes strongly prefer replication fork structures, 3′-flaps, and nicked HJs over intact HJs, and operate by a nick-and-counternick mechanism where the 5′ end of the nicked strand guides cleavage position—resolving debate about whether MUS81 is primarily an HJ resolvase or a fork-processing enzyme.

    Evidence Purified recombinant and endogenous enzymes from fission yeast, budding yeast, and human; defined oligonucleotide substrates; cleavage site mapping; meiotic crossover frequency analysis

    PMID:12084712 PMID:12473680 PMID:12686547 PMID:12721304 PMID:12724407 PMID:14527419 PMID:14527420 PMID:14704204

    Open questions at the time
    • In vivo substrates at stalled forks not directly visualized
    • Regulation of activity across cell cycle unknown
    • No structural information
  4. 2005 High

    Discovery that checkpoint kinase Cds1 phosphorylates Mus81 to dissociate it from chromatin during fork arrest, and that BLM helicase physically interacts with and stimulates Mus81 activity, established the first regulatory framework controlling when and how efficiently MUS81 cleaves replication intermediates.

    Evidence Phosphorylation analysis, chromatin fractionation, FHA-binding mutant in S. pombe; co-IP with domain mapping and in vitro stimulation assay for BLM-MUS81

    PMID:15805243 PMID:15805465

    Open questions at the time
    • Cell cycle timing of activation not defined
    • CDK/Polo regulation not yet discovered
    • In vivo fork cleavage not directly measured
  5. 2007 High

    Knockout studies in mammalian cells demonstrated that MUS81 is required for generating DSBs from stalled replication forks in vivo—including those blocked by interstrand crosslinks—converting the enzyme from a biochemically characterized nuclease to a defined cellular fork-processing factor.

    Evidence Mus81 knockout mouse ES cells, DSB measurement, replication fork recovery assays, ICL treatment, Rad54 epistasis

    PMID:17036055 PMID:17934473

    Open questions at the time
    • Which partner subunit (EME1 vs EME2) mediates S-phase function unknown
    • Mechanism of fork recognition in vivo unclear
  6. 2008 High

    Crystal structure of the Mus81-Eme1 complex revealed the heterodimeric architecture with a hydrophobic wedge separating duplex arms and a 5′-end binding pocket, providing the structural basis for preferential cleavage of nicked and flapped substrates.

    Evidence X-ray crystallography with functional mutagenesis validation

    PMID:18310322 PMID:18413719

    Open questions at the time
    • Structure of DNA-bound complex not yet available
    • EME2-containing complex not structurally characterized
  7. 2009 High

    Localization of MUS81 to ALT-associated PML bodies and demonstration that it promotes telomere recombination in a TRF2-regulated manner expanded MUS81 function beyond canonical replication fork repair to telomere maintenance in ALT cancer cells.

    Evidence Immunofluorescence co-localization, ChIP, siRNA, ALT recombination assays, co-IP with TRF2

    PMID:19363487

    Open questions at the time
    • Specific telomeric substrate structure unknown
    • Mechanism of TRF2 regulation of MUS81 activity not defined
  8. 2011 High

    Identification of Chk1 and Wee1 as negative regulators that protect stalled replication forks from untimely MUS81-EME1 cleavage established that the S-phase checkpoint directly restrains MUS81 nuclease access.

    Evidence siRNA co-depletion, co-IP of Wee1-MUS81, DSB quantification upon Chk1 inhibition, replication analysis

    PMID:21858151 PMID:21859861 PMID:22123861

    Open questions at the time
    • Direct phosphorylation of human MUS81 by Chk1/Wee1 not shown
    • Wee1-MUS81 interaction confirmed by single lab
  9. 2012 High

    Discovery that CDK and Polo-like kinase phosphorylate the Mms4/EME1 subunit to activate Mus81 nuclease strictly after bulk DNA synthesis established the central cell-cycle timing mechanism ensuring MUS81 acts only at the G2/M transition.

    Evidence Cell cycle-staged phosphorylation analysis, phospho-defective mutants, in vitro kinase and nuclease assays in S. cerevisiae; heterodimer solution analysis

    PMID:22645308 PMID:22730299

    Open questions at the time
    • Whether human EME1 phosphorylation follows identical logic not fully established
    • DDK contribution not yet recognized
  10. 2013 High

    Multiple convergent discoveries showed that MUS81-EME1 forms a SLX4-scaffolded holoenzyme with SLX1 at G2/M for HJ resolution, localizes to common fragile sites in early mitosis to resolve under-replicated DNA, and that premature Mus81 activation causes translocations—unifying temporal regulation with the two major G2/M functions of MUS81.

    Evidence In vitro reconstitution of SLX-MUS holoenzyme; CFS localization by immunofluorescence; phosphomimetic Mms4 mutant analysis; SLX4-null human cells with synthetic lethality; CDK/ATR phosphorylation of Eme1 in S. pombe

    PMID:23531881 PMID:23584455 PMID:23811685 PMID:23811686 PMID:24076221 PMID:24080495

    Open questions at the time
    • Structural basis for SLX4-mediated coordination of two active sites unknown
    • How MUS81-EME1 is specifically targeted to CFS loci not defined
  11. 2014 High

    Functional separation of MUS81-EME2 (S-phase fork restart, ALT telomeres) from MUS81-EME1 (G2/M HJ resolution, CFS processing) resolved the long-standing question of how a single catalytic subunit serves temporally distinct functions, and structural data on DNA-bound Mus81-Eme1 revealed the hydrophobic wedge and 5′-end pocket that explain substrate selectivity.

    Evidence Parallel siRNA depletion of EME1 vs EME2 with replication restart and ALT assays; comparative biochemistry of purified MUS81-EME1 vs MUS81-EME2; crystal structures of Mus81-Eme1-DNA complexes

    PMID:24371268 PMID:24733841 PMID:24813886

    Open questions at the time
    • No structure of MUS81-EME2
    • Mechanism of EME2-specific S-phase regulation unknown
  12. 2017 High

    Identification of DDK as an additional kinase required for Mus81-Mms4 activation via the Rtt107 scaffold, EZH2-mediated H3K27me3 as a chromatin signal recruiting MUS81 to stalled forks, and RECQ5 as a RAD51-displacing stimulator of MUS81 at CFS loci completed the upstream regulatory picture for MUS81 activation and substrate access.

    Evidence Kinase assays and co-IP for DDK/Rtt107; ChIP and inhibitor studies for EZH2/H3K27me3-MUS81 axis; co-IP, ChIP, and in vitro cleavage for RECQ5-MUS81

    PMID:28096179 PMID:28575661 PMID:29035360 PMID:29038425

    Open questions at the time
    • Whether EZH2-dependent recruitment applies beyond BRCA2-deficient contexts unclear
    • Direct DDK phosphorylation sites on human EME1/EME2 not mapped
  13. 2019 High

    Discovery that MUS81 cleavage of reversed forks at R-loops triggers ATR-Chk1 activation, which in turn limits further MUS81 cleavage, established a negative feedback loop linking MUS81 nucleolytic action to checkpoint signaling.

    Evidence siRNA depletion, ATR/Chk1 signaling assays, replication fork reversal analysis in human cells

    PMID:31708417

    Open questions at the time
    • Whether this feedback operates at all genomic loci or is R-loop-specific not known
    • Quantitative parameters of the feedback loop undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the SLX4-scaffolded SLX-MUS holoenzyme, how MUS81-EME2 is specifically regulated in S phase independently of CDK1/Cdc5, the identity of specific in vivo fork structures cleaved by MUS81 at single-molecule resolution, and whether MUS81-generated cytosolic DNA fragments contribute to innate immune signaling in physiological (non-cancer) contexts.
  • No cryo-EM or crystal structure of SLX-MUS holoenzyme
  • EME2-specific regulatory kinase not identified
  • In vivo fork substrates not visualized at nucleotide resolution
  • STING activation by MUS81-generated DNA confirmed in single cancer model only

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 12 GO:0016787 hydrolase activity 7 GO:0003677 DNA binding 3
Localization
GO:0005694 chromosome 4 GO:0005634 nucleus 2 GO:0005730 nucleolus 1
Pathway
R-HSA-73894 DNA Repair 9 R-HSA-1640170 Cell Cycle 6 R-HSA-69306 DNA Replication 6 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
BLMEME1EME2RAD54RECQ5SLX1SLX4TRF2
Complex memberships
MUS81-EME1MUS81-EME2SLX-MUS (SLX1-SLX4-MUS81-EME1)

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Mus81 and Eme1 form a heterodimeric endonuclease complex that resolves Holliday junctions into linear duplex products in fission yeast; both subunits are required for meiosis at a late step of meiotic recombination, and the meiotic defect is rescued by a bacterial HJ resolvase. Biochemical purification, in vitro HJ cleavage assay, genetic rescue with bacterial RusA resolvase Cell High 11719193
2001 Human Mus81-associated endonuclease cleaves synthetic Holliday junctions into linear duplexes by cutting strands of like polarity, and Mus81 protein abundance increases after agents that block DNA replication. In vitro endonuclease assay with oligonucleotide substrates, immunoblotting Molecular cell High 11741546
2000 Fission yeast Mus81 interacts with the FHA1 domain of checkpoint kinase Cds1, and mus81 inactivation causes hypersensitivity to replication stress, synthetic lethality with Rqh1 helicase loss, and meiotic defects; genetic epistasis places Mus81 in the recombination-based replication damage tolerance pathway. Two-hybrid interaction, genetic epistasis, phenotypic analysis of mus81 mutants Molecular and cellular biology High 11073977
2001 Budding yeast Mms4 and Mus81 form a heterodimeric structure-specific endonuclease; both subunits are required for optimal expression, substrate binding, and nuclease activity; the complex is 25-fold more active on branched duplex/replication fork substrates than on simple Y-forms. Co-immunoprecipitation, in vitro endonuclease assay, substrate specificity comparison Genes & development High 11641278
2003 Purified fission yeast Mus81-Eme1 preferentially cleaves replication fork structures and nicked junctions (D-loop/fork intermediates formed during DSB-to-dHJ transition) rather than intact HJs, and cleaves these in the orientation that guarantees crossover formation. Purified recombinant protein, in vitro cleavage assays with defined oligonucleotide substrates Molecular cell High 14527420
2003 Endogenous fission yeast Mus81-Eme1 resolves Holliday junctions by a nick-and-counternick mechanism: it preferentially cleaves nicked HJs, cutting the strand opposing the nick, and the second cut is rate-enhanced by the flexible nicked intermediate; HJs accumulate in a DNA polymerase alpha mutant lacking Mus81. Purification of endogenous complex, in vitro cleavage assays, genetic analysis Molecular cell High 14527419
2003 Human Mus81-Eme1 (hEME1 identified as the human EME1 homolog) forms a heterodimer with high specificity for synthetic replication fork structures and 3′-flaps; Holliday junctions are cleaved ~75-fold less efficiently than flap/fork structures. Purification of recombinant human Mus81-Eme1 heterodimer, in vitro substrate specificity assays The Journal of biological chemistry High 12721304
2003 Human MUS81 alone and MMS4 (human homolog identified) alone lack detectable nuclease activity; the hMUS81·hMMS4 complex is a structure-specific nuclease that resolves fork structures. Immunoaffinity purification, in vitro nuclease assays The Journal of biological chemistry High 12686547
2003 The Mus81-Mms4 cleavage site is determined by the 5′ end of the DNA strand at the flap junction (nicking 5 nt 5′ of the flap), not by the branch point, distinguishing it from Rad1-Rad10; substrates lacking a 5′ end near the flap are cleaved poorly by Mus81-Mms4. In vitro cleavage assays with defined substrates, mapping of cleavage sites Molecular and cellular biology High 12724407
2002 Fission yeast Mus81-Eme1 and budding yeast Mus81-Mms4 cleave regressed replication fork structures (lagging strand juxtaposed at junction, single-stranded tailed forks) but cleave intact HJs and normal forks poorly; cleavage maps 3–6 bp 5′ of the junction on the leading strand template. Purified recombinant enzymes, in vitro cleavage of defined replication fork substrates The Journal of biological chemistry High 12473680
2002 Purified recombinant fission yeast Mus81-Eme1 readily cleaves replication fork structures but cleaves synthetic HJs relatively poorly; genetic rescue of mus81/eme1/rqh1 mutant phenotypes by bacterial RusA supports an in vivo role in processing stalled/collapsed replication forks. Purified recombinant protein, in vitro cleavage, genetic rescue with RusA The Journal of biological chemistry High 12084712
2000 Saccharomyces cerevisiae Mus81 was identified by two-hybrid screen with Rad54 as bait; Mus81 and Rad54 interact in co-immunoprecipitation experiments; Mus81 contains XPF endonuclease superfamily and helix-hairpin-helix motifs; mus81Δ cells are sensitive to MMS and UV but not gamma-radiation. Two-hybrid screen, co-immunoprecipitation, genetic phenotypic analysis Molecular & general genetics High 10905349
2005 Checkpoint kinase Cds1 binds Mus81 via its FHA domain; Mus81 is phosphorylated in a Cds1-dependent manner; a mutation in the Mus81 FHA-binding motif eliminates Cds1 binding and phosphorylation, causes hyper-recombination and genome instability; upon HU-induced fork arrest, extensive Cds1-dependent phosphorylation of Mus81 causes its dissociation from chromatin, preventing cleavage of stalled forks. Genetic interaction, phosphorylation analysis, chromatin fractionation, mutant phenotype assays Genes & development High 15805465
2007 Mammalian Mus81 is required for formation of DNA double-strand breaks in response to replication inhibition; in Mus81-deficient cells, recovery of stalled replication forks is attenuated and chromosomal aberrations arise, indicating Mus81 converts replication-associated DNA structures into repair-amenable intermediates. Mus81 knockout mouse ES cells, DNA damage assays, replication fork recovery assays, cytogenetics Nature structural & molecular biology High 17934473
2006 Mouse Mus81-Eme1 endonuclease is responsible for generating ICL-induced DNA double-strand breaks in S phase; stalled replication forks are the in vivo substrates; Mus81 physically interacts with homologous recombination protein Rad54, and Mus81/Rad54 function in the same ICL repair pathway. Mus81-/- mouse ES cells, DSB measurement after crosslink treatment, co-immunoprecipitation, double-KO epistasis The EMBO journal High 17036055
2008 Crystal structure of the Mus81-Eme1 complex reveals each subunit has a nuclease domain, two HhH repeats, and a linker helix; a flexible 36-residue intradomain linker in Eme1 is essential for DNA recognition; basic residues in the active site cleft of Mus81 interact with the flexible arm of nicked HJ, providing structural basis for the nick-and-counternick mechanism. X-ray crystallography, biochemical mutagenesis Genes & development High 18413719
2008 Human Mus81-Eme1 catalyzes coordinate bilateral cleavage of model Holliday-junction structures sequentially within the lifetime of the enzyme-substrate complex; cooperative enzyme behavior results in symmetrical cruciform cleavage. Kinetic and enzymatic analysis of purified recombinant enzyme, self-limiting cruciform substrate assay Proceedings of the National Academy of Sciences of the United States of America High 18310322
2013 SLX1-SLX4 and MUS81-EME1 form a stable SLX-MUS holoenzyme at G2/M transition in response to CDK-mediated phosphorylation; SLX-MUS can be reconstituted in vitro and coordinates the active sites of both endonucleases for more efficient HJ resolution than SLX1-SLX4 alone. Co-immunoprecipitation, in vitro reconstitution, biochemical HJ cleavage assays, CDK phosphorylation analysis Molecular cell High 24076221
2013 MUS81-EME1 localizes to common fragile site (CFS) loci in early mitotic cells and actively promotes cytological CFS breaks; this cleavage is required for faithful sister chromatid disjunction. Live-cell imaging, immunofluorescence, MUS81-EME1 depletion, chromosome analysis Nature cell biology High 23811685
2013 MUS81-EME1 and ERCC1-XPF co-localize with FANCD2 at common fragile sites on mitotic chromosomes and process late replication intermediates/under-replicated DNA persisting at CFSs; their depletion increases anaphase bridges. Immunofluorescence on mitotic chromosomes, siRNA depletion, chromosome bridge quantification Nature cell biology High 23811686
2014 MUS81-EME2 (but not MUS81-EME1) is responsible for replication fork cleavage and restart in S phase in human cells; MUS81-EME2 also maintains telomeres in ALT cells; MUS81-EME1 handles G2/M functions (recombination intermediate cleavage, fragile site expression). siRNA depletion of EME1 vs EME2, replication fork restart assays, ALT telomere assays, cell cycle staging Cell reports High 24813886
2013 MUS81-EME2 substrate specificity differs from MUS81-EME1: MUS81-EME2 is more active, cleaves D-loop intermediates by cutting the 3′-invading strand, and cleaves 5′-flap structures; both cleave 3′-flaps, replication forks, and nicked HJs; neither cleaves intact HJs efficiently. Purified recombinant MUS81-EME2 and MUS81-EME1, comparative in vitro cleavage assays Nucleic acids research High 24371268
2014 Crystal structures of human Mus81-Eme1 bound to flap DNA substrates reveal substrate-induced conformational changes; a hydrophobic wedge of Mus81 separates pre- and post-nick duplex DNA, and a '5′ end binding pocket' hosts the nicked-end of post-nick DNA, explaining preferential cleavage of 3′-flap substrates with 5′ nicked ends. X-ray crystallography, biochemical and biophysical validation The EMBO journal High 24733841
2008 Saccharomyces cerevisiae Mus81-Mms4 exists as a single heterodimer (not a higher-order multimer) in solution, when bound to DNA, and in vivo by co-immunoprecipitation; Cdc5 kinase activates Mus81-Mms4 nuclease activity on 3′-flaps and HJs in vitro but does not induce multimerization or a preference for intact HJs, supporting a model of cleavage of nicked intermediates. Solution biochemistry, EM imaging, Co-IP, in vitro kinase activation assays Molecular and cellular biology High 22645308
2012 Budding yeast Mus81-Mms4 nuclease activity is strictly regulated by CDK (Cdc28) and Polo-like kinase (Cdc5)-dependent phosphorylation of the non-catalytic Mms4 subunit; phosphorylation occurs only after bulk DNA synthesis and before chromosome segregation; phosphorylation-defective mms4 mutants show highly reduced nuclease activity. Cell cycle-staged phosphorylation analysis, phospho-defective mutants, in vitro and in vivo nuclease assays Nucleic acids research High 22730299
2013 Premature activation of the Cdk1/Cdc5/Mus81 pathway via phosphomimetic Mms4 variants or in S-phase checkpoint-deficient backgrounds causes aberrant replication and crossover-associated chromosome translocations, establishing that temporal restriction of Mus81-Mms4 to late G2/M is essential for genome stability. Phosphomimetic mutants, genetic analysis, chromosome rearrangement assays The EMBO journal High 23531881
2017 Cdc7-Dbf4 (DDK) kinase, together with Cdc5 (Polo), phosphorylates Mus81-Mms4 in an interdependent manner; DDK-mediated phosphorylation of Mms4 is strictly required for Mus81 activation in mitosis; the scaffold protein Rtt107 binds Mus81-Mms4 and recruits DDK and Cdc5 to the complex for full activation. Kinase assays, co-immunoprecipitation, phospho-defective mutants, genetic analysis The EMBO journal High 28096179
2013 DNA damage-induced activation of fission yeast Mus81-Eme1 requires both Cdc2(CDK1)- and Rad3(ATR)-dependent phosphorylation of Eme1; this activation prevents gross chromosomal rearrangements in rqh1-deficient cells. Phosphorylation analysis, ATR/CDK mutant genetics, GCR assay Nature structural & molecular biology High 23584455
2011 In human cells, Wee1 interacts physically with Mus81, and co-depletion of Mus81 abrogates the S-phase delay caused by Wee1 deficiency, indicating that Wee1 directly controls Mus81 to protect stalled replication fork stability. Co-immunoprecipitation, siRNA co-depletion, S-phase progression analysis The Journal of cell biology Medium 21859861
2011 Mus81-Eme1 endonuclease is responsible for generating DSBs when Chk1 is inactivated in human cells; Mus81/Eme1-dependent DNA damage—rather than global fork stalling—causes incomplete replication; Chk1 normally protects replication forks from Mus81-Eme1 cleavage. siRNA depletion, DNA damage quantification, replication analysis PloS one High 21858151
2011 Mus81-Eme1 cleaves replication forks stalled by topoisomerase I-DNA complexes (Top1cc), generating DSBs that allow replication fork progression and cell survival; Mus81 cleaves the stalled fork rather than excising the Top1cc. Mus81 knockdown, DNA combing, DSB assays after camptothecin treatment The Journal of cell biology High 22123861
2017 EZH2 localizes at stalled replication forks, methylates H3K27, and thereby recruits MUS81 nuclease to the fork; low EZH2 reduces H3K27 methylation, prevents MUS81 recruitment, and causes fork stabilization; this EZH2→H3K27me3→MUS81 axis promotes fork degradation in BRCA2-deficient cells. ChIP, H3K27me3 analysis, MUS81 recruitment assays, EZH2 depletion/inhibition Nature cell biology High 29035360
2017 In BRCA2-deficient cells, MRE11-initiated and EXO1-extended resection of regressed fork arms creates a ssDNA tail substrate for MUS81; MUS81 cleavage then promotes POLD3-dependent fork rescue after genotoxic withdrawal. DNA fiber assays, genetic epistasis, nuclease depletion experiments Nature communications High 29038425
2019 In response to aberrant R-loop accumulation, MUS81 endonuclease is required for ATR-Chk1 pathway activation via reversed replication forks; ATR in turn prevents excessive MUS81 cleavage of reversed forks, constituting a MUS81-triggered negative feedback loop. siRNA depletion, ATR/Chk1 signaling assays, replication fork reversal analysis Molecular cell High 31708417
2017 RECQ5 helicase physically interacts with MUS81, is recruited to CFS loci in early mitosis in a CDK1-Ser727 phosphorylation-dependent manner, and promotes MUS81-EME1 cleavage by displacing RAD51 filaments that otherwise inhibit 3′-flap cleavage. Co-immunoprecipitation, ChIP, siRNA, phosphomutant analysis, in vitro cleavage assay Molecular cell High 28575661
2009 MUS81 localizes specifically to ALT-associated PML nuclear bodies (APBs) and associates with telomeric DNA in ALT cells during G2 phase; MUS81 depletion reduces telomere recombination; MUS81's endonuclease activity and its interaction with TRF2 (which regulates this activity) are required for ALT cell survival. Immunofluorescence co-localization, ChIP, siRNA, ALT-specific recombination assays, Co-IP Nature cell biology High 19363487
2003 Mus81 endonuclease localizes to nucleoli and to regions of UV damage specifically in S-phase human cells; BLM and WRN helicases co-localize with Mus81 in nucleoli; Mus81 protein peaks in abundance during S phase. Immunofluorescence, cell cycle staging, co-localization with BLM/WRN Molecular biology of the cell Medium 14638871
2005 BLM helicase physically interacts with Mus81 (amino acids 125–244 of Mus81 interact with BLM C-terminus aa 1007–1417) in vivo and co-localizes at stalled replication forks; BLM stimulates Mus81 endonuclease activity on nicked HJs and 3′-flaps by enhancing Mus81 binding to DNA substrates. Co-immunoprecipitation, domain mapping, in vitro stimulation assay, immunofluorescence Cancer research High 15805243
2008 Human Rad54 stimulates human Mus81-Eme1 endonuclease activity on HJ-like substrates through specific protein-protein interaction; stimulation requires Rad54-DNA complex formation with ATP and is species-specific (yeast Rad54 does not stimulate human Mus81-Eme1). Purified proteins, in vitro stimulation assay, specificity controls Proceedings of the National Academy of Sciences of the United States of America High 19017809
2016 MUS81 endonuclease cleaves genomic DNA generating cytosolic dsDNA; this cytosolic DNA activates the STING-dependent type I interferon pathway, promoting immune rejection of prostate cancer cells; PARP-dependent repair pathways cooperate with MUS81 in this process. MUS81 knockdown/KO, cytosolic DNA quantification, STING signaling assays, immune cell assays Immunity Medium 27178469
2016 MUS81 negatively regulates WEE1 protein levels by promoting its ubiquitination via E3 ligase β-TRCP in an enzymatic (nuclease activity-dependent) manner in gastric cancer cells. Co-IP, ubiquitination assays, nuclease-dead mutant analysis Journal of experimental & clinical cancer research Medium 34625086
2015 Mus81 endonuclease promotes replication fork progression and reduces replication initiation frequency during normal growth; Mus81-deficient cells replicate more slowly and use origins at higher frequency without activating new origin pools. DNA combing, BrdU incorporation, replication fork speed measurement in Mus81-/- cells Nature communications Medium 25879486
2008 Fission yeast Mus81 is essential for sister chromatid recombination at broken replication forks; it is the dedicated endonuclease resolving sister chromatid recombination intermediates during one-ended DSB repair; Swi9/Swi10 handles ectopic sequence-based repair. Genetic analysis, molecular evidence for sister recombination intermediates, epistasis The EMBO journal High 18388861
2003 Fission yeast mus81 mutants have 20- to 100-fold reduced meiotic crossover frequencies but normal or elevated gene conversion, genetically separating these two outcomes and placing Mus81 specifically in the crossover pathway. Genetic analysis of crossover and gene conversion frequencies in mus81 mutants Genetics High 14704204
2016 In Chk1-deficient cells, MUS81-EME2 (not MUS81-EME1) is responsible for nuclease-dependent DNA damage and DSB formation; this damage activates ATM signaling, which in turn modulates replication fork speed and origin usage. EME1 vs EME2 specific depletion, ATM pathway analysis, replication dynamics Cell reports Medium 26804904
2013 In human SLX4-null cells, HJ resolution requires both SLX4-associated MUS81-EME1 and SLX1 acting in concert; loss of both SLX4 and BLM or GEN1 and SLX4 is synthetically lethal due to unprocessed HJs causing defective mitosis. Human SLX4-null cell line, synthetic lethality analysis, chromosome analysis Cell reports High 24080495

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Mus81-Eme1 are essential components of a Holliday junction resolvase. Cell 454 11719193
2017 MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells. Nature communications 339 29038425
2007 The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks. Nature structural & molecular biology 325 17934473
2003 The Mus81/Mms4 endonuclease acts independently of double-Holliday junction resolution to promote a distinct subset of crossovers during meiosis in budding yeast. Genetics 309 12750322
2017 EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nature cell biology 280 29035360
2002 Alternate pathways involving Sgs1/Top3, Mus81/ Mms4, and Srs2 prevent formation of toxic recombination intermediates from single-stranded gaps created by DNA replication. Proceedings of the National Academy of Sciences of the United States of America 274 12475932
2001 Functional overlap between Sgs1-Top3 and the Mms4-Mus81 endonuclease. Genes & development 267 11641278
2003 Generating crossovers by resolution of nicked Holliday junctions: a role for Mus81-Eme1 in meiosis. Molecular cell 258 14527420
2013 Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells. Molecular cell 255 24076221
2006 The structure-specific endonuclease Mus81-Eme1 promotes conversion of interstrand DNA crosslinks into double-strands breaks. The EMBO journal 243 17036055
2000 Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1. Molecular and cellular biology 238 11073977
2013 ERCC1 and MUS81-EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis. Nature cell biology 235 23811686
2008 Structural and functional relationships of the XPF/MUS81 family of proteins. Annual review of biochemistry 231 18518821
2013 MUS81 promotes common fragile site expression. Nature cell biology 229 23811685
2001 Human Mus81-associated endonuclease cleaves Holliday junctions in vitro. Molecular cell 229 11741546
2002 Mus81-Eme1 and Rqh1 involvement in processing stalled and collapsed replication forks. The Journal of biological chemistry 203 12084712
2000 MUS81 encodes a novel helix-hairpin-helix protein involved in the response to UV- and methylation-induced DNA damage in Saccharomyces cerevisiae. Molecular & general genetics : MGG 193 10905349
2016 The DNA Structure-Specific Endonuclease MUS81 Mediates DNA Sensor STING-Dependent Host Rejection of Prostate Cancer Cells. Immunity 183 27178469
2003 Identification and characterization of the human mus81-eme1 endonuclease. The Journal of biological chemistry 175 12721304
2015 DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage. Science (New York, N.Y.) 167 26273056
2011 Wee1 controls genomic stability during replication by regulating the Mus81-Eme1 endonuclease. The Journal of cell biology 162 21859861
2008 MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis. PLoS genetics 161 18787696
2004 Involvement of mammalian Mus81 in genome integrity and tumor suppression. Science (New York, N.Y.) 160 15205536
2003 The mechanism of Mus81-Mms4 cleavage site selection distinguishes it from the homologous endonuclease Rad1-Rad10. Molecular and cellular biology 159 12724407
2003 The endogenous Mus81-Eme1 complex resolves Holliday junctions by a nick and counternick mechanism. Molecular cell 149 14527419
2011 Mus81-mediated DNA cleavage resolves replication forks stalled by topoisomerase I-DNA complexes. The Journal of cell biology 142 22123861
2010 Mus81 and Yen1 promote reciprocal exchange during mitotic recombination to maintain genome integrity in budding yeast. Molecular cell 140 21172663
2008 RecQ helicase, Sgs1, and XPF family endonuclease, Mus81-Mms4, resolve aberrant joint molecules during meiotic recombination. Molecular cell 138 18691965
2005 Disruption of murine Mus81 increases genomic instability and DNA damage sensitivity but does not promote tumorigenesis. Molecular and cellular biology 123 16107704
2013 Cooperative control of holliday junction resolution and DNA repair by the SLX1 and MUS81-EME1 nucleases. Molecular cell 122 24076219
2013 Human GEN1 and the SLX4-associated nucleases MUS81 and SLX1 are essential for the resolution of replication-induced Holliday junctions. Cell reports 119 24080495
2019 ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop. Molecular cell 118 31708417
2008 Mus81/Mms4 endonuclease and Sgs1 helicase collaborate to ensure proper recombination intermediate metabolism during meiosis. Molecular cell 117 18691964
2014 Roles of SLX1-SLX4, MUS81-EME1, and GEN1 in avoiding genome instability and mitotic catastrophe. Genes & development 114 24831703
2013 Premature Cdk1/Cdc5/Mus81 pathway activation induces aberrant replication and deleterious crossover. The EMBO journal 114 23531881
2007 Exploring the roles of Mus81-Eme1/Mms4 at perturbed replication forks. DNA repair 114 17409028
2005 Replication checkpoint kinase Cds1 regulates Mus81 to preserve genome integrity during replication stress. Genes & development 109 15805465
2014 MUS81-EME2 promotes replication fork restart. Cell reports 107 24813886
2012 Cell cycle-dependent regulation of the nuclease activity of Mus81-Eme1/Mms4. Nucleic acids research 105 22730299
2002 Cleavage of model replication forks by fission yeast Mus81-Eme1 and budding yeast Mus81-Mms4. The Journal of biological chemistry 102 12473680
2003 Fission yeast Mus81.Eme1 Holliday junction resolvase is required for meiotic crossing over but not for gene conversion. Genetics 100 14704204
2011 Structure-specific DNA endonuclease Mus81/Eme1 generates DNA damage caused by Chk1 inactivation. PloS one 96 21858151
2008 Mus81 is essential for sister chromatid recombination at broken replication forks. The EMBO journal 95 18388861
2008 Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway. The Journal of cell biology 93 18852298
2017 MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells. Nature communications 92 28714477
2017 RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis. Molecular cell 91 28575661
2003 X-ray and biochemical anatomy of an archaeal XPF/Rad1/Mus81 family nuclease: similarity between its endonuclease domain and restriction enzymes. Structure (London, England : 1993) 90 12679022
2010 Functional overlap between the structure-specific nucleases Yen1 and Mus81-Mms4 for DNA-damage repair in S. cerevisiae. DNA repair 83 20106725
2009 Telomere recombination requires the MUS81 endonuclease. Nature cell biology 82 19363487
2010 RAD5A, RECQ4A, and MUS81 have specific functions in homologous recombination and define different pathways of DNA repair in Arabidopsis thaliana. The Plant cell 81 20971895
2013 FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress. Nature communications 80 23361013
2013 Combinatorial regulation of meiotic holliday junction resolution in C. elegans by HIM-6 (BLM) helicase, SLX-4, and the SLX-1, MUS-81 and XPF-1 nucleases. PLoS genetics 80 23901331
2008 Saccharomyces cerevisiae Mus81-Mms4 is a catalytic, DNA structure-selective endonuclease. Nucleic acids research 80 18281703
2004 DNA repair by a Rad22-Mus81-dependent pathway that is independent of Rhp51. Nucleic acids research 78 15486206
2005 Substrate specificity of the Saccharomyces cerevisiae Mus81-Mms4 endonuclease. DNA repair 75 15590332
2001 The fuss about Mus81. Cell 75 11733053
2007 Cleavage of stalled forks by fission yeast Mus81/Eme1 in absence of DNA replication checkpoint. Molecular biology of the cell 68 18032583
2013 Survival of the replication checkpoint deficient cells requires MUS81-RAD52 function. PLoS genetics 64 24204313
2016 Signaling from Mus81-Eme2-Dependent DNA Damage Elicited by Chk1 Deficiency Modulates Replication Fork Speed and Origin Usage. Cell reports 63 26804904
2013 Joint molecule resolution requires the redundant activities of MUS-81 and XPF-1 during Caenorhabditis elegans meiosis. PLoS genetics 60 23874209
2008 Cleavage mechanism of human Mus81-Eme1 acting on Holliday-junction structures. Proceedings of the National Academy of Sciences of the United States of America 60 18310322
2007 Bloom's syndrome helicase and Mus81 are required to induce transient double-strand DNA breaks in response to DNA replication stress. Journal of molecular biology 59 18054789
2012 Distinct roles of Mus81, Yen1, Slx1-Slx4, and Rad1 nucleases in the repair of replication-born double-strand breaks by sister chromatid exchange. Molecular and cellular biology 58 22354996
2010 Overlapping roles for Yen1 and Mus81 in cellular Holliday junction processing. The Journal of biological chemistry 58 20178992
2006 Haploinsufficiency of the Mus81-Eme1 endonuclease activates the intra-S-phase and G2/M checkpoints and promotes rereplication in human cells. Nucleic acids research 58 16456034
2015 The DNA repair endonuclease Mus81 facilitates fast DNA replication in the absence of exogenous damage. Nature communications 56 25879486
2008 Mus81-dependent double-strand DNA breaks at in vivo-generated cruciform structures in S. cerevisiae. Molecular cell 56 18922464
2009 Retracted: Cooperativity of Mus81.Mms4 with Rad54 in the resolution of recombination and replication intermediates. The Journal of biological chemistry 55 19129197
2013 Regulation of Mus81-Eme1 Holliday junction resolvase in response to DNA damage. Nature structural & molecular biology 54 23584455
2012 Mus81-Mms4 functions as a single heterodimer to cleave nicked intermediates in recombinational DNA repair. Molecular and cellular biology 54 22645308
2008 Crystal structure of the Mus81-Eme1 complex. Genes & development 54 18413719
2003 Identification and characterization of human MUS81-MMS4 structure-specific endonuclease. The Journal of biological chemistry 53 12686547
2017 Dbf4-dependent kinase and the Rtt107 scaffold promote Mus81-Mms4 resolvase activation during mitosis. The EMBO journal 52 28096179
2010 The archaeal Xpf/Mus81/FANCM homolog Hef and the Holliday junction resolvase Hjc define alternative pathways that are essential for cell viability in Haloferax volcanii. DNA repair 52 20667794
2013 Substrate specificity of the MUS81-EME2 structure selective endonuclease. Nucleic acids research 49 24371268
2009 The human Holliday junction resolvase GEN1 rescues the meiotic phenotype of a Schizosaccharomyces pombe mus81 mutant. Nucleic acids research 48 20040574
2014 Controlling meiotic recombinational repair - specifying the roles of ZMMs, Sgs1 and Mus81/Mms4 in crossover formation. PLoS genetics 47 25329811
2005 Structural and functional analyses of an archaeal XPF/Rad1/Mus81 nuclease: asymmetric DNA binding and cleavage mechanisms. Structure (London, England : 1993) 47 16084390
2003 Mus81 endonuclease localizes to nucleoli and to regions of DNA damage in human S-phase cells. Molecular biology of the cell 46 14638871
2007 Synthetic lethality of Drosophila in the absence of the MUS81 endonuclease and the DmBlm helicase is associated with elevated apoptosis. Genetics 44 17603121
2005 BLM helicase facilitates Mus81 endonuclease activity in human cells. Cancer research 44 15805243
2012 The WRN and MUS81 proteins limit cell death and genome instability following oncogene activation. Oncogene 42 22410776
2003 RNA interference inhibition of Mus81 reduces mitotic recombination in human cells. Molecular biology of the cell 42 14617801
2014 Mus81-Mms4 and Yen1 resolve a novel anaphase bridge formed by noncanonical Holliday junctions. Nature communications 38 25466415
2009 Two distinct MUS81-EME1 complexes from Arabidopsis process Holliday junctions. Plant physiology 38 19339504
2004 An archaeal endonuclease displays key properties of both eukaryal XPF-ERCC1 and Mus81. The Journal of biological chemistry 36 15591065
2016 STC2 as a novel mediator for Mus81-dependent proliferation and survival in hepatocellular carcinoma. Cancer letters 35 27939696
2021 Targeting MUS81 promotes the anticancer effect of WEE1 inhibitor and immune checkpoint blocking combination therapy via activating cGAS/STING signaling in gastric cancer cells. Journal of experimental & clinical cancer research : CR 34 34625086
2016 SLX4-SLX1 Protein-independent Down-regulation of MUS81-EME1 Protein by HIV-1 Viral Protein R (Vpr). The Journal of biological chemistry 34 27354282
2008 Human Rad54 protein stimulates human Mus81-Eme1 endonuclease. Proceedings of the National Academy of Sciences of the United States of America 34 19017809
2008 Mus81, Rhp51(Rad51), and Rqh1 form an epistatic pathway required for the S-phase DNA damage checkpoint. Molecular biology of the cell 34 19037101
2005 Roles of SGS1, MUS81, and RAD51 in the repair of lagging-strand replication defects in Saccharomyces cerevisiae. Current genetics 34 16193328
2014 Crystal structures of the structure-selective nuclease Mus81-Eme1 bound to flap DNA substrates. The EMBO journal 33 24733841
2016 Disruption of SLX4-MUS81 Function Increases the Relative Biological Effectiveness of Proton Radiation. International journal of radiation oncology, biology, physics 32 27084631
2020 Mus81-Eme1-dependent aberrant processing of DNA replication intermediates in mitosis impairs genome integrity. Science advances 31 33298441
2013 Mus81 nuclease and Sgs1 helicase are essential for meiotic recombination in a protist lacking a synaptonemal complex. Nucleic acids research 31 23935123
2020 Homologous recombination and Mus81 promote replication completion in response to replication fork blockage. EMBO reports 30 32419301
2014 Human MUS81-EME2 can cleave a variety of DNA structures including intact Holliday junction and nicked duplex. Nucleic acids research 30 24692662
2015 Hold your horSSEs: controlling structure-selective endonucleases MUS81 and Yen1/GEN1. Frontiers in genetics 29 26284109
2013 Temporal regulation of the Mus81-Mms4 endonuclease ensures cell survival under conditions of DNA damage. Nucleic acids research 29 23901010