Gene Symbol: MMS4
Description: Mms4p
Alias: SLX2, YBR100W, Mms4p
Species: Saccharomyces cerevisiae S288c

Top Publications

  1. Muñoz Galvan S, Tous C, Blanco M, Schwartz E, Ehmsen K, West S, et al. Distinct roles of Mus81, Yen1, Slx1-Slx4, and Rad1 nucleases in the repair of replication-born double-strand breaks by sister chromatid exchange. Mol Cell Biol. 2012;32:1592-603 pubmed publisher
    ..We analyzed the functional relevance of four structure-selective endonucleases (SSEs), Yen1, Mus81-Mms4, Slx1-Slx4, and Rad1, on SCR in Saccharomyces cerevisiae...
  2. Mullen J, Kaliraman V, Ibrahim S, Brill S. Requirement for three novel protein complexes in the absence of the Sgs1 DNA helicase in Saccharomyces cerevisiae. Genetics. 2001;157:103-18 pubmed
    ..Analysis of the null mutants identified a pair of genes in each of three phenotypic classes. Mutations in MMS4 (SLX2) and SLX3 generate identical phenotypes, including weak UV and strong MMS hypersensitivity, complete loss of ..
  3. Blanco M, Matos J, Rass U, Ip S, West S. Functional overlap between the structure-specific nucleases Yen1 and Mus81-Mms4 for DNA-damage repair in S. cerevisiae. DNA Repair (Amst). 2010;9:394-402 pubmed publisher
    ..These findings indicate that Yen1 can act upon recombination/repair intermediates that arise in MUS81-defective cells following replication fork damage. ..
  4. Fabre F, Chan A, Heyer W, Gangloff S. Alternate pathways involving Sgs1/Top3, Mus81/ Mms4, and Srs2 prevent formation of toxic recombination intermediates from single-stranded gaps created by DNA replication. Proc Natl Acad Sci U S A. 2002;99:16887-92 pubmed
    ..Here, we identify a similar interaction involving double mutations affecting Sgs1 or Top3 and Mus81 or Mms4. We also find that the primary DNA structures that initiate these toxic recombination events cannot be double-..
  5. Zakharyevich K, Tang S, Ma Y, Hunter N. Delineation of joint molecule resolution pathways in meiosis identifies a crossover-specific resolvase. Cell. 2012;149:334-47 pubmed publisher
    ..remain uncertain, but three distinct endonucleases capable of resolving JMs in vitro have been identified: Mus81-Mms4(EME1), Slx1-Slx4(BTBD12), and Yen1(GEN1)...
  6. Gaskell L, Osman F, Gilbert R, Whitby M. Mus81 cleavage of Holliday junctions: a failsafe for processing meiotic recombination intermediates?. EMBO J. 2007;26:1891-901 pubmed
    ..purification of active forms of recombinant Schizosaccharomyces pombe Mus81-Eme1 and Saccharomyces cerevisiae Mus81-Mms4, which display robust HJ cleavage in vitro, which, in the case of Mus81-Eme1, is as good as the archetypal HJ ..
  7. Kang M, Lee C, Kang Y, Cho I, Nguyen T, Seo Y. Genetic and functional interactions between Mus81-Mms4 and Rad27. Nucleic Acids Res. 2010;38:7611-25 pubmed publisher
    ..Mus81-Mms4 is a structure-specific endonuclease that can resolve stalled replication forks as well as toxic recombination ..
  8. Gallo Fernández M, Saugar I, Ortiz Bazan M, Vázquez M, Tercero J. Cell cycle-dependent regulation of the nuclease activity of Mus81-Eme1/Mms4. Nucleic Acids Res. 2012;40:8325-35 pubmed
    The conserved heterodimeric endonuclease Mus81-Eme1/Mms4 plays an important role in the maintenance of genomic integrity in eukaryotic cells...
  9. Torres Rosell J, Machin F, Farmer S, Jarmuz A, Eydmann T, Dalgaard J, et al. SMC5 and SMC6 genes are required for the segregation of repetitive chromosome regions. Nat Cell Biol. 2005;7:412-9 pubmed
    ..These results point towards a role for the Smc5-Smc6 complex in preventing the formation of sister chromatid junctions, thereby ensuring the correct partitioning of chromosomes during anaphase. ..

More Information


  1. Fu Y, Xiao W. Functional domains required for the Saccharomyces cerevisiae Mus81-Mms4 endonuclease complex formation and nuclear localization. DNA Repair (Amst). 2003;2:1435-47 pubmed
    The Saccharomyces cerevisiae Mms4 and Mus81 proteins form a specific complex, which functions as an endonuclease specific for branched DNA molecules and protects cells from killing by DNA alkylation damage, but not damage induced by ..
  2. Argueso J, Wanat J, Gemici Z, Alani E. Competing crossover pathways act during meiosis in Saccharomyces cerevisiae. Genetics. 2004;168:1805-16 pubmed
    In Saccharomyces cerevisiae the MSH4-MSH5, MLH1-MLH3, and MUS81-MMS4 complexes act to promote crossing over during meiosis. MSH4-MSH5, but not MUS81-MMS4, promotes crossovers that display interference...
  3. Kaliraman V, Mullen J, Fricke W, Bastin Shanower S, Brill S. Functional overlap between Sgs1-Top3 and the Mms4-Mus81 endonuclease. Genes Dev. 2001;15:2730-40 pubmed
    ..We have shown previously that yeast cells lacking SGS1 or TOP3 require MMS4 and MUS81 for viability...
  4. de los Santos T, Loidl J, Larkin B, Hollingsworth N. A role for MMS4 in the processing of recombination intermediates during meiosis in Saccharomyces cerevisiae. Genetics. 2001;159:1511-25 pubmed
    The MMS4 gene of Saccharomyces cerevisiae was originally identified due to its sensitivity to MMS in vegetative cells. Subsequent studies have confirmed a role for MMS4 in DNA metabolism of vegetative cells...
  5. Xiao W, Chow B, Milo C. Mms4, a putative transcriptional (co)activator, protects Saccharomyces cerevisiae cells from endogenous and environmental DNA damage. Mol Gen Genet. 1998;257:614-23 pubmed
    b>mms4-1 is one of several Saccharomyces cerevisiae mutants that exhibit an increased sensitivity to methyl methanesulfonate (MMS), but not to UV or X-rays...
  6. Jessop L, Lichten M. Mus81/Mms4 endonuclease and Sgs1 helicase collaborate to ensure proper recombination intermediate metabolism during meiosis. Mol Cell. 2008;31:313-23 pubmed publisher
    Budding yeast lacking the Sgs1 helicase and the Mus81/Mms4 endonuclease are inviable, and indirect studies implicate homologous recombination gone awry as the cause of death...
  7. Ehmsen K, Heyer W. Saccharomyces cerevisiae Mus81-Mms4 is a catalytic, DNA structure-selective endonuclease. Nucleic Acids Res. 2008;36:2182-95 pubmed publisher
    The DNA structure-selective endonuclease Mus81-Mms4/Eme1 is a context-specific recombination factor that supports DNA replication, but is not essential for DSB repair in Saccharomyces cerevisiae. We overexpressed Mus81-Mms4 in S...
  8. De Muyt A, Jessop L, Kolar E, Sourirajan A, Chen J, Dayani Y, et al. BLM helicase ortholog Sgs1 is a central regulator of meiotic recombination intermediate metabolism. Mol Cell. 2012;46:43-53 pubmed publisher
    ..form by late HJ intermediate resolution, using an alternate pathway requiring the overlapping activities of Mus81-Mms4, Yen1, and Slx1-Slx4, nucleases with minor roles in wild-type meiosis...
  9. Szakal B, Branzei D. Premature Cdk1/Cdc5/Mus81 pathway activation induces aberrant replication and deleterious crossover. EMBO J. 2013;32:1155-67 pubmed publisher
    ..G2/M damage checkpoint-independent, but Cdk1/Cdc5-dependent pathway that proceeds via a previously described Mus81-Mms4-activating phosphorylation...
  10. Ehmsen K, Heyer W. A junction branch point adjacent to a DNA backbone nick directs substrate cleavage by Saccharomyces cerevisiae Mus81-Mms4. Nucleic Acids Res. 2009;37:2026-36 pubmed publisher
    The DNA structure-selective endonuclease Mus81-Mms4/Eme1 incises a number of nicked joint molecule substrates in vitro. 3'-flaps are an excellent in vitro substrate for Mus81-Mms4/Eme1...
  11. Matos J, Blanco M, Maslen S, Skehel J, West S. Regulatory control of the resolution of DNA recombination intermediates during meiosis and mitosis. Cell. 2011;147:158-72 pubmed publisher
    ..In yeast meiosis, Mus81-Mms4 and Yen1 are controlled by phosphorylation events that lead to their sequential activation...
  12. Mullen J, Nallaseth F, Lan Y, Slagle C, Brill S. Yeast Rmi1/Nce4 controls genome stability as a subunit of the Sgs1-Top3 complex. Mol Cell Biol. 2005;25:4476-87 pubmed the SGS1-TOP3 pathway, based on the observation that strains lacking any one of these genes require MUS81 and MMS4 for viability...
  13. Ashton T, Mankouri H, Heidenblut A, McHugh P, Hickson I. Pathways for Holliday junction processing during homologous recombination in Saccharomyces cerevisiae. Mol Cell Biol. 2011;31:1921-33 pubmed publisher
    ..Deletion of SGS1, TOP3, or RMI1 is synthetically lethal when combined with the loss of the Mus81-Mms4 or Slx1-Slx4 endonucleases, which have been implicated in Holliday junction (HJ) resolution...
  14. Mancera E, Bourgon R, Brozzi A, Huber W, Steinmetz L. High-resolution mapping of meiotic crossovers and non-crossovers in yeast. Nature. 2008;454:479-85 pubmed publisher
    ..In addition, because non-crossover hotspots create holes of reduced linkage within haplotype blocks, our results stress the need to incorporate non-crossovers into genetic linkage analysis...
  15. Oh S, Lao J, Taylor A, Smith G, Hunter N. RecQ helicase, Sgs1, and XPF family endonuclease, Mus81-Mms4, resolve aberrant joint molecules during meiotic recombination. Mol Cell. 2008;31:324-36 pubmed publisher
    Saccharomyces cerevisiae RecQ helicase, Sgs1, and XPF family endonuclease, Mus81-Mms4, are implicated in processing joint molecule (JM) recombination intermediates...
  16. Agmon N, Yovel M, Harari Y, Liefshitz B, Kupiec M. The role of Holliday junction resolvases in the repair of spontaneous and induced DNA damage. Nucleic Acids Res. 2011;39:7009-19 pubmed publisher yeast has shown HJ resolution activity for a protein called Yen1, in addition to the previously known Mus81/Mms4 complex...
  17. Sonntag Brown M, Lim E, Chen C, Nishant K, Alani E. Genetic analysis of mlh3 mutations reveals interactions between crossover promoting factors during meiosis in baker's yeast. G3 (Bethesda). 2013;3:9-22 pubmed publisher
    ..crossing over and meiotic viability, we analyzed crossing over on four chromosomes of varying lengths in mlh3? mms4? strains and observed strong decreases (6- to 17-fold) in crossing over in all intervals...
  18. Schwartz E, Wright W, Ehmsen K, Evans J, Stahlberg H, Heyer W. Mus81-Mms4 functions as a single heterodimer to cleave nicked intermediates in recombinational DNA repair. Mol Cell Biol. 2012;32:3065-80 pubmed publisher
    The formation of crossovers is a fundamental genetic process. The XPF-family endonuclease Mus81-Mms4 (Eme1) contributes significantly to crossing over in eukaryotes...
  19. Zanders S, Alani E. The pch2Delta mutation in baker's yeast alters meiotic crossover levels and confers a defect in crossover interference. PLoS Genet. 2009;5:e1000571 pubmed publisher
    ..Third, crossovers observed in pch2Delta require both Msh4-Msh5 and Mms4-Mus81 functions...
  20. Gritenaite D, Princz L, Szakal B, Bantele S, Wendeler L, Schilbach S, et al. A cell cycle-regulated Slx4-Dpb11 complex promotes the resolution of DNA repair intermediates linked to stalled replication. Genes Dev. 2014;28:1604-19 pubmed publisher
    ..Here, we identify a regulatory mechanism in yeast that critically controls JM resolution by the Mus81-Mms4 endonuclease...
  21. Matos J, Blanco M, West S. Cell-cycle kinases coordinate the resolution of recombination intermediates with chromosome segregation. Cell Rep. 2013;4:76-86 pubmed publisher
    ..kinases Cdk and Cdc5 in coordinating these events through their involvement in the phosphoregulation of the Mus81-Mms4 nuclease...
  22. Coluccio A, Malzone M, Neiman A. Genetic evidence of a role for membrane lipid composition in the regulation of soluble NEM-sensitive factor receptor function in Saccharomyces cerevisiae. Genetics. 2004;166:89-97 pubmed
    ..These results indicate that elevated levels of phosphatidic acid in the membrane may be required specifically for the function of SNARE complexes containing Spo20p. ..
  23. Keyamura K, Arai K, Hishida T. Srs2 and Mus81-Mms4 Prevent Accumulation of Toxic Inter-Homolog Recombination Intermediates. PLoS Genet. 2016;12:e1006136 pubmed publisher
    ..The structure-specific complex of crossover junction endonucleases Mus81 and Mms4 was also required for viability of diploid, but not haploid, SRS2 deletion mutants (srs2?), and diploid srs2? mus81?..
  24. Mazon G, Symington L. Mph1 and Mus81-Mms4 prevent aberrant processing of mitotic recombination intermediates. Mol Cell. 2013;52:63-74 pubmed publisher
    ..cerevisiae Mph1 helicase prevents crossovers between ectopic sequences by removing substrates for Mus81-Mms4 or Rad1-Rad10 cleavage. A role for Yen1 is only apparent in the absence of Mus81...
  25. Ölmezer G, Klein D, Rass U. DNA repair defects ascribed to pby1 are caused by disruption of Holliday junction resolvase Mus81-Mms4. DNA Repair (Amst). 2015;33:17-23 pubmed publisher
    ..On the basis of genetic interaction profile similarity, we pinpoint disruption of Holliday junction resolvase Mus81-Mms4 as the mutation responsible for DNA repair phenotypes currently ascribed to pby1...
  26. Chang M, Bellaoui M, Zhang C, Desai R, Morozov P, Delgado Cruzata L, et al. RMI1/NCE4, a suppressor of genome instability, encodes a member of the RecQ helicase/Topo III complex. EMBO J. 2005;24:2024-33 pubmed
    ..In addition, rmi1Delta strains fail to fully activate Rad53 upon exposure to DNA-damaging agents, suggesting that Rmi1 is also an important part of the Rad53-dependent DNA damage response. ..
  27. Xaver M, Huang L, Chen D, Klein F. Smc5/6-Mms21 prevents and eliminates inappropriate recombination intermediates in meiosis. PLoS Genet. 2013;9:e1004067 pubmed publisher
    ..JMs that escape the ZMM pathway and BLM/Sgs1 are eliminated before metaphase by resolvases like Mus81-Mms4 to prevent chromosome nondisjunction...
  28. Bonetti D, Anbalagan S, Lucchini G, Clerici M, Longhese M. Tbf1 and Vid22 promote resection and non-homologous end joining of DNA double-strand break ends. EMBO J. 2013;32:275-89 pubmed publisher
    ..Finally, inactivation of either Tbf1 or Vid22 impairs nucleosome eviction around the DSB, suggesting that these proteins promote efficient repair of the break by influencing chromatin identity in its surroundings. ..
  29. Princz L, Wild P, Bittmann J, Aguado F, Blanco M, Matos J, et al. Dbf4-dependent kinase and the Rtt107 scaffold promote Mus81-Mms4 resolvase activation during mitosis. EMBO J. 2017;36:664-678 pubmed publisher
    ..In case of budding yeast Mus81-Mms4, this cell cycle stage-specific activation is known to depend on phosphorylation by CDK and Cdc5 kinases...
  30. Hwang J, Smith S, Myung K. The Rad1-Rad10 complex promotes the production of gross chromosomal rearrangements from spontaneous DNA damage in Saccharomyces cerevisiae. Genetics. 2005;169:1927-37 pubmed
    ..Results presented here suggest that Rad1-Rad10 functions at different stages of GCR formation and that there is an alternative pathway for the GCR formation that is independent of Rad1-Rad10. ..
  31. Oke A, Anderson C, Yam P, Fung J. Controlling meiotic recombinational repair - specifying the roles of ZMMs, Sgs1 and Mus81/Mms4 in crossover formation. PLoS Genet. 2014;10:e1004690 pubmed publisher
    ..Moreover, detailed examination of conversion tracts in sgs1 and mms4-md mutants reveal distinct aberrant recombination events involving multiple chromatid invasions...
  32. Chin J, Bashkirov V, Heyer W, Romesberg F. Esc4/Rtt107 and the control of recombination during replication. DNA Repair (Amst). 2006;5:618-28 pubmed
    ..Thus, we propose that Esc4 associates with ssDNA of stalled forks and acts as a scaffolding protein to recruit and/or modulate the function of other proteins required to reinitiate DNA synthesis. ..
  33. Xue X, Choi K, Bonner J, Chiba T, Kwon Y, Xu Y, et al. Restriction of replication fork regression activities by a conserved SMC complex. Mol Cell. 2014;56:436-45 pubmed publisher
    ..Our findings provide molecular insights into replication fork repair regulation and uncover a role of Smc5-Smc6 in directing Mph1 activity toward a specific biochemical outcome. ..
  34. Scheller J, Schürer A, Rudolph C, Hettwer S, Kramer W. MPH1, a yeast gene encoding a DEAH protein, plays a role in protection of the genome from spontaneous and chemically induced damage. Genetics. 2000;155:1069-81 pubmed
    ..mph1 slightly increased the UV sensitivity of mms2, rad6, and rad14 mutants, but no effect on X-ray sensitivity was observed. These data suggest that MPH1 is not part of a hitherto known repair pathway. Possible functions are discussed. ..
  35. Chakraborty P, Pankajam A, Lin G, Dutta A, Krishnaprasad N, Tekkedil M, et al. Modulating Crossover Frequency and Interference for Obligate Crossovers in Saccharomyces cerevisiae Meiosis. G3 (Bethesda). 2017;7:1511-1524 pubmed publisher
    ..other resolvase mutants showed that most of the crossovers in mlh3? pch2? are made through the Mus81-Mms4 pathway...
  36. Garcia Luis J, Clemente Blanco A, Aragon L, Machin F. Cdc14 targets the Holliday junction resolvase Yen1 to the nucleus in early anaphase. Cell Cycle. 2014;13:1392-9 pubmed publisher
    ..instead, other structure-specific endonucleases (SSE) that recognize branched DNA play the leading roles, Mus81-Mms4/EME1 being the most important in budding yeast...
  37. Copsey A, Tang S, Jordan P, Blitzblau H, Newcombe S, Chan A, et al. Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions. PLoS Genet. 2013;9:e1004071 pubmed publisher
    ..we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4(Eme1)...
  38. Mukherjee S, Wright W, Ehmsen K, Heyer W. The Mus81-Mms4 structure-selective endonuclease requires nicked DNA junctions to undergo conformational changes and bend its DNA substrates for cleavage. Nucleic Acids Res. 2014;42:6511-22 pubmed publisher
    Mus81-Mms4/EME1 is a DNA structure-selective endonuclease that cleaves joint DNA molecules that form during homologous recombination in mitotic and meiotic cells...
  39. García Luis J, Machín F. Mus81-Mms4 and Yen1 resolve a novel anaphase bridge formed by noncanonical Holliday junctions. Nat Commun. 2014;5:5652 pubmed publisher
    ..Here we report that the overlapping actions of the structure-selective endonucleases (SSEs) Mus81-Mms4/EME1 and Yen1/GEN1, but not Slx1-Slx4, are also essential to prevent the formation of spontaneous SCBs that depend ..
  40. Cussiol J, Jablonowski C, Yimit A, Brown G, Smolka M. Dampening DNA damage checkpoint signalling via coordinated BRCT domain interactions. EMBO J. 2015;34:1704-17 pubmed publisher
    ..MBD also interacts with the Mus81 nuclease following checkpoint dampening, suggesting a spatio-temporal coordination of checkpoint signalling and DNA repair via a combinatorial mode of BRCT-domains interactions. ..
  41. Matulova P, Marini V, Burgess R, Sisakova A, Kwon Y, Rothstein R, et al. Cooperativity of Mus81.Mms4 with Rad54 in the resolution of recombination and replication intermediates. J Biol Chem. 2009;284:7733-45 pubmed publisher
    The Saccharomyces cerevisiae Mus81.Mms4 protein complex, a DNA structure-specific endonuclease, helps preserve genomic integrity by resolving pathological DNA structures that arise from damaged or aborted replication forks and may also ..
  42. Herrero A, Moreno S. Lsm1 promotes genomic stability by controlling histone mRNA decay. EMBO J. 2011;30:2008-18 pubmed publisher
    ..Our results demonstrate that improper histone stoichiometry leads to genomic instability and highlight the importance of regulating histone mRNA decay in the tight control of histone levels in yeast. ..
  43. Panico E, Ede C, Schildmann M, Schürer K, Kramer W. Genetic evidence for a role of Saccharomyces cerevisiae Mph1 in recombinational DNA repair under replicative stress. Yeast. 2010;27:11-27 pubmed publisher
    ..Finally, we observe an epistatic relationship in terms of sensitivity to camptothecin of mms4 or mus81 to mph1. Overall, our results support a role of Mph1 in assisting replication progression...
  44. Saugar I, V zquez M, Gallo Fern ndez M, Ortiz Baz n M, Segurado M, Calzada A, et al. Temporal regulation of the Mus81-Mms4 endonuclease ensures cell survival under conditions of DNA damage. Nucleic Acids Res. 2013;41:8943-58 pubmed publisher
    The structure-specific Mus81-Eme1/Mms4 endonuclease contributes importantly to DNA repair and genome integrity maintenance...
  45. Chavdarova M, Marini V, Sisakova A, Sedlackova H, Vigasová D, Brill S, et al. Srs2 promotes Mus81-Mms4-mediated resolution of recombination intermediates. Nucleic Acids Res. 2015;43:3626-42 pubmed publisher
    ..The structure-specific endonuclease Mus81-Mms4 has been implicated in processing DNA intermediates that arise from collapsed forks and homologous recombination...
  46. Yakir Tamang L, Gerst J. A phosphatidylinositol-transfer protein and phosphatidylinositol-4-phosphate 5-kinase control Cdc42 to regulate the actin cytoskeleton and secretory pathway in yeast. Mol Biol Cell. 2009;20:3583-97 pubmed publisher
    ..Based upon these findings, we propose that the exocytic signal involves PI delivery to the PI kinases (i.e., Mss4) by Sfh5, generation of PI(4,5)P(2), and PI(4,5)P(2)-dependent regulation of Cdc42 and the actin cytoskeleton. ..
  47. Sebesta M, Urulangodi M, Stefanovie B, Szakal B, Pacesa M, Lisby M, et al. Esc2 promotes Mus81 complex-activity via its SUMO-like and DNA binding domains. Nucleic Acids Res. 2017;45:215-230 pubmed publisher
    ..Here we show interaction between Esc2 and a structure-specific endonuclease Mus81-Mms4 (the Mus81 complex), their involvement in the metabolism of SCJs, and the effects Esc2 has on the enzymatic ..
  48. Nitiss K, Malik M, He X, White S, Nitiss J. Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage. Proc Natl Acad Sci U S A. 2006;103:8953-8 pubmed
    ..Our results show that Tdp1 plays more general roles in DNA repair than repair of Top1 mediated DNA damage, and may participate in repairing many types of base damage to DNA. ..
  49. Odagiri N, Seki M, Onoda F, Yoshimura A, Watanabe S, Enomoto T. Budding yeast mms4 is epistatic with rad52 and the function of Mms4 can be replaced by a bacterial Holliday junction resolvase. DNA Repair (Amst). 2003;2:347-58 pubmed
    b>MMS4 of Saccharomyces cerevisiae was originally identified as the gene responsible for one of the collection of methyl methanesulfonate (MMS)-sensitive mutants, mms4...