id: P87231
gene_symbol: mus81
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:284812
  label: Schizosaccharomyces pombe (strain 972 / ATCC 24843)
description: >-
  Mus81 is the catalytic subunit of the Mus81-Eme1 structure-specific DNA
  endonuclease of fission yeast, a member of the XPF/ERCC4 nuclease family. It
  carries an ERCC4 nuclease domain (residues ~331-429) with an essential
  catalytic aspartate pair (Asp395-Asp396) and requires Mg2+ as cofactor. In an
  obligate heterodimer with Eme1, Mus81 cleaves branched DNA structures with a
  free 5'-end at the branch point, including nicked Holliday junctions (its
  preferred substrate), 3'-flaps, D-loops, model replication forks, and intact
  Holliday junctions (as a backup activity). Through this activity it resolves
  recombination intermediates and joint molecules, processes stalled and
  collapsed replication forks, and contributes to double-strand break repair.
  Mus81-Eme1 is the principal nuclear resolvase generating meiotic crossovers in
  S. pombe, where most or all crossovers depend on it because the alternative
  MSH4-MSH5 crossover pathway is absent; crossovers in turn establish chiasmata
  required for accurate meiotic chromosome segregation. Mus81 is nuclear, and its
  activity is regulated by the cell cycle and by the replication checkpoint kinase
  Cds1, with which it physically interacts via the Cds1 FHA1 domain, contributing
  to the S-phase DNA damage/replication-slowing checkpoint.
existing_annotations:
- term:
    id: GO:0008821
    label: crossover junction DNA endonuclease activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: |-
      Phylogenetic (IBA) propagation of the core molecular function of Mus81 across the
      orthology group. This is the central catalytic activity of Mus81-Eme1, directly
      demonstrated experimentally in S. pombe, so the IBA call is well-founded.
    action: ACCEPT
    reason: Core molecular function, corroborated by direct experimental evidence (IDA/IMP) in S. pombe.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: We report that Mus81 and an associated protein Eme1 are components of an endonuclease that resolves Holliday junctions into linear duplex products.
      reference_section_type: ABSTRACT
- term:
    id: GO:0048476
    label: Holliday junction resolvase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: |-
      Phylogenetic propagation of complex membership. Mus81 is part of the Mus81-Eme1
      heterodimeric resolvase, established experimentally in S. pombe.
    action: ACCEPT
    reason: Core cellular component, corroborated by direct experimental IDA/IPI evidence for the Mus81-Eme1 complex.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: These findings constitute strong evidence that Mus81 and Eme1 are subunits of a nuclear Holliday junction resolvase.
      reference_section_type: ABSTRACT
- term:
    id: GO:0000712
    label: resolution of meiotic recombination intermediates
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: |-
      Phylogenetic propagation of a core meiotic biological process. Mus81-Eme1 resolves
      meiotic joint molecules/Holliday junctions at a late step of meiotic recombination,
      directly shown in S. pombe.
    action: ACCEPT
    reason: Core meiotic process, corroborated by direct and mutant-phenotype evidence in S. pombe.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: Mus81 and Eme1 are required during meiosis at a late step of meiotic recombination.
      reference_section_type: ABSTRACT
- term:
    id: GO:0000727
    label: double-strand break repair via break-induced replication
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: |-
      IBA propagation of a role in break-induced/recombination-dependent replication. Mus81-Eme1
      processes collapsed replication forks and the joint molecules formed during
      recombination-dependent fork restart, consistent with a BIR-related role, though the
      direct S. pombe evidence is for fork processing rather than canonical BIR. Plausible but
      a peripheral, non-core aspect.
    action: KEEP_AS_NON_CORE
    reason: Consistent with Mus81 fork/joint-molecule processing but not the central function; BIR involvement is inferred rather than directly demonstrated for S. pombe Mus81.
    supported_by:
    - reference_id: PMID:28586299
      supporting_text: The heterodimeric structure-specific DNA endonuclease Mus81-Eme1 can cleave both stalled RFs and recombination intermediates, including D-loops and Holliday junctions
      reference_section_type: RESULTS
- term:
    id: GO:0031573
    label: mitotic intra-S DNA damage checkpoint signaling
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: |-
      IBA propagation of a role in the intra-S DNA damage checkpoint. In S. pombe Mus81 acts
      downstream of Cds1 in checkpoint-dependent replication slowing, corroborated by direct
      mutant analysis.
    action: ACCEPT
    reason: Corroborated by IMP evidence (PMID:19037101) placing Mus81 in the Cds1-dependent S-phase DNA damage checkpoint pathway.
    supported_by:
    - reference_id: PMID:19037101
      supporting_text: We have identified proteins downstream of Cds1 required for checkpoint-dependant slowing, including the structure-specific endonuclease Mus81 and the helicase Rqh1
      reference_section_type: ABSTRACT
- term:
    id: GO:0000712
    label: resolution of meiotic recombination intermediates
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: |-
      ARBA machine-learning electronic annotation duplicating the experimentally supported core
      meiotic process. Accurate but redundant with the IDA/IMP/IBA calls for the same term.
    action: ACCEPT
    reason: Correct core process, redundant with stronger experimental evidence in S. pombe.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: Mus81 and Eme1 are required during meiosis at a late step of meiotic recombination.
      reference_section_type: ABSTRACT
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: |-
      ARBA electronic annotation for DSB repair via HR. This is supported experimentally in
      S. pombe, where Mus81 processes recombination intermediates and its loss impairs repair
      of MMS-induced DSBs.
    action: ACCEPT
    reason: Correct, corroborated by IMP evidence (PMID:17307401, PMID:17363897).
    supported_by:
    - reference_id: PMID:17307401
      supporting_text: In Deltamus7 and Deltamus81 cells, the repair of MMS-induced DNA double-strand breaks (DSBs) is severely impaired.
      reference_section_type: ABSTRACT
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: |-
      InterPro2GO electronic annotation. Mus81 binds branched DNA substrates (it contains a
      winged-helix/HhH DNA-binding region in addition to the ERCC4 nuclease domain), so DNA
      binding is correct but generic; the specific structure-specific endonuclease activity is
      more informative.
    action: KEEP_AS_NON_CORE
    reason: True but generic; subsumed by the more specific crossover junction DNA endonuclease activity.
    supported_by:
    - reference_id: PMID:14527419
      supporting_text: a nicked HJ is the preferred substrate of endogenous and recombinant Mus81-Eme1
      reference_section_type: ABSTRACT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: |-
      Electronic annotation from the UniProt Subcellular Location mapping. Mus81 is a nuclear
      protein, consistent with its role in chromosomal DNA repair and the experimental
      localization reported in the primary literature.
    action: ACCEPT
    reason: Correct core localization, corroborated by experimental subcellular localization in S. pombe.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: These findings constitute strong evidence that Mus81 and Eme1 are subunits of a nuclear Holliday junction resolvase.
      reference_section_type: ABSTRACT
- term:
    id: GO:0006302
    label: double-strand break repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: |-
      InterPro2GO electronic annotation for DSB repair. Supported by experimental S. pombe
      evidence (IMP); the more specific HR child term is also annotated.
    action: ACCEPT
    reason: Correct, corroborated by IMP evidence (PMID:11719193, PMID:17307401).
    supported_by:
    - reference_id: PMID:17307401
      supporting_text: In Deltamus7 and Deltamus81 cells, the repair of MMS-induced DNA double-strand breaks (DSBs) is severely impaired.
      reference_section_type: ABSTRACT
- term:
    id: GO:0006308
    label: DNA catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: |-
      InterPro2GO electronic annotation. Although Mus81 is a nuclease, "DNA catabolic process"
      is misleading for a structure-specific endonuclease whose biological role is resolving
      recombination/replication intermediates rather than bulk DNA degradation. The
      endonucleolytic incisions are part of DNA repair/recombination, not catabolism.
    action: REMOVE
    reason: Over-broad/misleading IEA; Mus81 makes precise resolving incisions in repair/recombination, not DNA degradation. The biology is captured by the recombination and repair BP terms.
    supported_by:
    - reference_id: PMID:14527419
      supporting_text: Cleavage occurs specifically on the strand that opposes the nick, resulting in resolution of the structure into linear duplex products.
      reference_section_type: ABSTRACT
- term:
    id: GO:0008821
    label: crossover junction DNA endonuclease activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: |-
      Combined-IEA electronic annotation of the core endonuclease activity, duplicating the
      experimentally established function.
    action: ACCEPT
    reason: Correct core MF, redundant with strong experimental evidence.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: We report that Mus81 and an associated protein Eme1 are components of an endonuclease that resolves Holliday junctions into linear duplex products.
      reference_section_type: ABSTRACT
- term:
    id: GO:0031297
    label: replication fork processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: |-
      ARBA electronic annotation for replication fork processing, a well-supported core role in
      S. pombe (also annotated by IMP). Mus81-Eme1 cleaves stalled/collapsed forks and the
      branched intermediates that arise during fork repair and termination.
    action: ACCEPT
    reason: Correct core process, corroborated by IMP evidence (PMID:28586299).
    supported_by:
    - reference_id: PMID:28586299
      supporting_text: The heterodimeric structure-specific DNA endonuclease Mus81-Eme1 can cleave both stalled RFs and recombination intermediates, including D-loops and Holliday junctions
      reference_section_type: RESULTS
- term:
    id: GO:0043596
    label: nuclear replication fork
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: |-
      ARBA electronic annotation placing Mus81 at the nuclear replication fork. This is
      consistent with its fork-processing role and is also supported by an IDA call
      (PMID:17363897 via ComplexPortal); Mus81-Eme1 acts on fork structures. A reasonable,
      if context-dependent, localization (it is recruited to forks/aberrant structures rather
      than constitutively fork-resident).
    action: KEEP_AS_NON_CORE
    reason: Consistent with fork-associated activity but Mus81 is a damage/structure-recruited nuclease rather than a constitutive fork component; the core localization term is nucleus.
    supported_by:
    - reference_id: PMID:28586299
      supporting_text: The heterodimeric structure-specific DNA endonuclease Mus81-Eme1 can cleave both stalled RFs and recombination intermediates, including D-loops and Holliday junctions
      reference_section_type: RESULTS
- term:
    id: GO:0048476
    label: Holliday junction resolvase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: |-
      ARBA electronic annotation of complex membership, duplicating the experimentally
      established Mus81-Eme1 resolvase complex.
    action: ACCEPT
    reason: Correct core CC, redundant with IDA/IPI evidence.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: These findings constitute strong evidence that Mus81 and Eme1 are subunits of a nuclear Holliday junction resolvase.
      reference_section_type: ABSTRACT
- term:
    id: GO:0007131
    label: reciprocal meiotic recombination
  evidence_type: IDA
  original_reference_id: PMID:17363897
  qualifier: involved_in
  review:
    summary: |-
      Direct (ComplexPortal) annotation that Mus81-Eme1 promotes meiotic crossovers (reciprocal
      recombination). The study purified active recombinant S. pombe Mus81-Eme1 with robust HJ
      cleavage and provided genetic evidence for its meiotic CO function; in fission yeast most
      or all crossovers depend on Mus81.
    action: ACCEPT
    reason: Core meiotic process directly supported; fission yeast crossovers are essentially Mus81-dependent.
    supported_by:
    - reference_id: PMID:17363897
      supporting_text: in the fission yeast Schizosaccharomyces pombe most, if not all, COs depend on Mus81
      reference_section_type: INTRODUCTION
- term:
    id: GO:0043596
    label: nuclear replication fork
  evidence_type: IDA
  original_reference_id: PMID:17363897
  qualifier: located_in
  review:
    summary: |-
      ComplexPortal IDA placing Mus81-Eme1 at the nuclear replication fork, reflecting its
      ability to bind and cleave fork structures. Mus81-Eme1 acts on replication-fork and
      fork-derived joint structures in mitotic cells.
    action: KEEP_AS_NON_CORE
    reason: Reflects fork-associated activity; Mus81 is recruited to fork/branched structures rather than being a constitutive fork resident. Core localization is nucleus.
    supported_by:
    - reference_id: PMID:17363897
      supporting_text: Mus81-Eme1 also functions in mitotic cells to promote the repair of DNA interstrand crosslinks and stalled and broken replication forks
      reference_section_type: DISCUSSION
- term:
    id: GO:0048476
    label: Holliday junction resolvase complex
  evidence_type: IPI
  original_reference_id: PMID:17363897
  qualifier: part_of
  review:
    summary: |-
      Physical-interaction (ComplexPortal IPI) evidence that Mus81 is part of the Mus81-Eme1
      resolvase complex, the obligate heterodimer that cleaves Holliday junctions and other
      branched substrates.
    action: ACCEPT
    reason: Core CC, supported by purification of the active Mus81-Eme1 heterodimer.
    supported_by:
    - reference_id: PMID:17363897
      supporting_text: we report the purification of active forms of recombinant Schizosaccharomyces pombe Mus81-Eme1
      reference_section_type: ABSTRACT
- term:
    id: GO:0032042
    label: mitochondrial DNA metabolic process
  evidence_type: IC
  original_reference_id: GO_REF:0000111
  qualifier: involved_in
  review:
    summary: |-
      Curator-inferred (IC) annotation combining the high-throughput mitochondrial localization
      call (GO:0005739, HDA from PMID:16823372) with the endonuclease activity (GO:0008821) to
      infer a role in mitochondrial DNA metabolism. There is no direct functional evidence for
      a mitochondrial DNA role of Mus81 in S. pombe, and the mitochondrial signal derives from a
      single genome-wide YFP localization study that is prone to false positives. All
      experimentally characterized functions of Mus81 are nuclear (meiotic CO resolution,
      replication-fork and recombination intermediate processing).
    action: MARK_AS_OVER_ANNOTATED
    reason: Speculative inference resting on a noise-prone HDA localization datum and the generic nuclease activity; no functional evidence supports a mitochondrial DNA role for Mus81.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: These findings constitute strong evidence that Mus81 and Eme1 are subunits of a nuclear Holliday junction resolvase.
      reference_section_type: ABSTRACT
- term:
    id: GO:0031297
    label: replication fork processing
  evidence_type: IMP
  original_reference_id: PMID:28586299
  qualifier: involved_in
  review:
    summary: |-
      Mutant-phenotype evidence that Mus81 is required for processing of converging/collapsed
      replication forks. Loss of mus81 reduces spacer-dependent deletions arising during fork
      termination, and recombinant Mus81-Eme1 cleaves a model inter-fork-strand-annealing
      junction in vitro (catalytic-dead mutant cannot). Strong support for a core
      fork-processing role.
    action: ACCEPT
    reason: Core process directly supported by mutant phenotype plus in vitro junction-cleavage assay.
    supported_by:
    - reference_id: PMID:28586299
      supporting_text: loss of mus81 causes a > 2 fold reduction in SDDs in strains with either a 2 or 5 kb centromere-proximal spacer DNA (Figure 4B), indicating that Mus81-Eme1 specifically promotes SDDs.
      reference_section_type: RESULTS
- term:
    id: GO:0007131
    label: reciprocal meiotic recombination
  evidence_type: IGI
  original_reference_id: PMID:25414342
  qualifier: involved_in
  review:
    summary: |-
      Genetic-interaction evidence that Mus81-Eme1-dependent crossovers are promoted by
      Rad51/Dmc1 paralog/mediator complexes (e.g. Swi5-Sfr1) that antagonize the Fml1 and Rqh1
      helicases. Reinforces the core meiotic crossover role of Mus81.
    action: ACCEPT
    reason: Core meiotic process supported by genetic-interaction analysis.
    supported_by:
    - reference_id: PMID:25414342
      supporting_text: play a major role in antagonizing both the FANCM-family DNA helicase/translocase Fml1 and the RecQ-type DNA helicase Rqh1 to limit hybrid DNA formation and promote Mus81-Eme1-dependent COs.
      reference_section_type: ABSTRACT
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IMP
  original_reference_id: PMID:17307401
  qualifier: involved_in
  review:
    summary: |-
      Mutant-phenotype evidence that Mus81 functions in repair of replication-associated DSBs.
      mus81 deletion (like mus7 deletion in the same pathway) severely impairs repair of
      MMS-induced DSBs, consistent with a role in HR-mediated repair of replication-associated
      breaks.
    action: ACCEPT
    reason: Core repair process supported by mutant phenotype in S. pombe.
    supported_by:
    - reference_id: PMID:17307401
      supporting_text: In Deltamus7 and Deltamus81 cells, the repair of MMS-induced DNA double-strand breaks (DSBs) is severely impaired.
      reference_section_type: ABSTRACT
- term:
    id: GO:0006302
    label: double-strand break repair
  evidence_type: IMP
  original_reference_id: PMID:11719193
  qualifier: involved_in
  review:
    summary: |-
      Mutant-phenotype evidence (from the founding Mus81-Eme1 resolvase study) that Mus81 is
      required for DSB repair, specifically the resolution of recombination intermediates
      (Holliday junctions) arising during meiotic and damage-induced recombination.
    action: ACCEPT
    reason: Core repair process; well supported by mutant analysis and the resolvase mechanism.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: Mus81, a fission yeast protein related to the XPF subunit of ERCC1-XPF nucleotide excision repair endonuclease, is essential for meiosis and important for coping with stalled replication forks.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11719193
  qualifier: enables
  review:
    summary: |-
      IPI annotation recording the physical interaction with Eme1 (SPAPB1E7.06c). The
      interaction is genuine and biologically central (Mus81 and Eme1 form the obligate
      heterodimeric endonuclease), but "protein binding" is uninformative. The relationship is
      better represented by the Holliday junction resolvase complex (GO:0048476) cellular
      component term, which is already annotated.
    action: MODIFY
    reason: "Avoid uninformative protein binding; the Mus81-Eme1 interaction is captured by the complex CC term."
    proposed_replacement_terms:
    - id: GO:0048476
      label: Holliday junction resolvase complex
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: We report that Mus81 and an associated protein Eme1 are components of an endonuclease that resolves Holliday junctions into linear duplex products.
      reference_section_type: ABSTRACT
- term:
    id: GO:0000712
    label: resolution of meiotic recombination intermediates
  evidence_type: IDA
  original_reference_id: PMID:11719193
  qualifier: involved_in
  review:
    summary: |-
      Direct-assay evidence that Mus81-Eme1 resolves Holliday junctions into linear duplex
      products, the biochemical activity underlying resolution of meiotic recombination
      intermediates. Core process.
    action: ACCEPT
    reason: Core meiotic process directly demonstrated by the resolvase activity assay.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: We report that Mus81 and an associated protein Eme1 are components of an endonuclease that resolves Holliday junctions into linear duplex products.
      reference_section_type: ABSTRACT
- term:
    id: GO:0000712
    label: resolution of meiotic recombination intermediates
  evidence_type: IMP
  original_reference_id: PMID:11719193
  qualifier: involved_in
  review:
    summary: |-
      Mutant-phenotype support for the same core meiotic process: mus81 mutants are defective at
      a late step of meiotic recombination, and the meiotic defect is rescued by a bacterial
      Holliday junction resolvase, demonstrating that the missing function is junction resolution.
    action: ACCEPT
    reason: Core meiotic process supported by the cross-complementation (bacterial resolvase rescue) experiment.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: The mus81 meiotic defect is rescued by expression of a bacterial Holliday junction resolvase.
      reference_section_type: ABSTRACT
- term:
    id: GO:0000712
    label: resolution of meiotic recombination intermediates
  evidence_type: IGI
  original_reference_id: PMID:11719193
  qualifier: involved_in
  review:
    summary: |-
      Genetic-interaction support (with eme1, SPAC17A5.11, and a further partner) for the same
      core meiotic resolution process. Mus81 and Eme1 act together in resolving meiotic
      recombination intermediates.
    action: ACCEPT
    reason: Core meiotic process supported by genetic interaction with its obligate partner eme1.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: Mus81 and Eme1 are required during meiosis at a late step of meiotic recombination.
      reference_section_type: ABSTRACT
- term:
    id: GO:0008821
    label: crossover junction DNA endonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:11719193
  qualifier: enables
  review:
    summary: |-
      Direct-assay evidence for the core molecular function: Mus81-Eme1 is an endonuclease that
      cleaves (crossover/Holliday) junction DNA into linear duplex products.
    action: ACCEPT
    reason: Core molecular function directly demonstrated.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: We report that Mus81 and an associated protein Eme1 are components of an endonuclease that resolves Holliday junctions into linear duplex products.
      reference_section_type: ABSTRACT
- term:
    id: GO:0008821
    label: crossover junction DNA endonuclease activity
  evidence_type: IMP
  original_reference_id: PMID:11719193
  qualifier: enables
  review:
    summary: |-
      Mutant-phenotype support for the core endonuclease function. The catalytic DD->AA mutant
      (Asp395-Asp396) abrogates endonuclease activity, linking the activity to Mus81's ERCC4
      catalytic residues.
    action: ACCEPT
    reason: Core molecular function; the catalytic-site mutant confirms Mus81 contributes the nuclease activity.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: Mus81, a fission yeast protein related to the XPF subunit of ERCC1-XPF nucleotide excision repair endonuclease, is essential for meiosis and important for coping with stalled replication forks.
      reference_section_type: ABSTRACT
- term:
    id: GO:0048476
    label: Holliday junction resolvase complex
  evidence_type: IDA
  original_reference_id: PMID:11719193
  qualifier: part_of
  review:
    summary: |-
      Direct evidence that Mus81 is a subunit of the nuclear Holliday junction resolvase
      complex (Mus81-Eme1). Core cellular component.
    action: ACCEPT
    reason: Core CC directly demonstrated.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: These findings constitute strong evidence that Mus81 and Eme1 are subunits of a nuclear Holliday junction resolvase.
      reference_section_type: ABSTRACT
- term:
    id: GO:0031573
    label: mitotic intra-S DNA damage checkpoint signaling
  evidence_type: IMP
  original_reference_id: PMID:19037101
  qualifier: involved_in
  review:
    summary: |-
      Mutant-phenotype evidence that Mus81 is required for checkpoint-dependent slowing of DNA
      replication in response to damage, acting downstream of Cds1 in an epistatic pathway with
      Rhp51 and Rqh1. Supports a role in the intra-S DNA damage checkpoint.
    action: ACCEPT
    reason: Supported by mutant analysis placing Mus81 in the Cds1-dependent S-phase DNA damage checkpoint pathway.
    supported_by:
    - reference_id: PMID:19037101
      supporting_text: defining an epistatic pathway in which mus81 is epistatic to rhp51 and rhp51 is epistatic to rqh1.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:16823372
  qualifier: is_active_in
  review:
    summary: |-
      High-throughput YFP localization (genome-wide ORFeome study) detecting Mus81 in the
      nucleus. Consistent with all functional data: Mus81 acts on chromosomal DNA in the
      nucleus.
    action: ACCEPT
    reason: Correct core localization, concordant with experimental and curated nuclear localization.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: These findings constitute strong evidence that Mus81 and Eme1 are subunits of a nuclear Holliday junction resolvase.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:16823372
  qualifier: is_active_in
  review:
    summary: |-
      High-throughput YFP localization call placing Mus81 in the mitochondrion. This derives
      from a single genome-wide localization screen and is not corroborated by any functional
      study; all characterized Mus81 functions are nuclear (meiotic crossover resolution,
      replication-fork and recombination-intermediate processing). Such genome-wide screens are
      prone to false-positive organellar signals.
    action: MARK_AS_OVER_ANNOTATED
    reason: Unsupported by any functional evidence; isolated high-throughput localization datum inconsistent with the nuclear biology of Mus81.
    supported_by:
    - reference_id: PMID:11719193
      supporting_text: These findings constitute strong evidence that Mus81 and Eme1 are subunits of a nuclear Holliday junction resolvase.
      reference_section_type: ABSTRACT
- term:
    id: GO:0033314
    label: mitotic DNA replication checkpoint signaling
  evidence_type: IMP
  original_reference_id: PMID:11073977
  qualifier: involved_in
  review:
    summary: |-
      Mutant-phenotype evidence that Mus81 contributes to checkpoint control associated with
      replication stress: inactivation of mus81 triggers a checkpoint-dependent delay of
      mitosis, and Mus81 interacts with the FHA1 domain of the replication checkpoint kinase
      Cds1. Supports a role in replication-stress checkpoint signaling.
    action: ACCEPT
    reason: Supported by mutant phenotype and physical interaction with the Cds1 checkpoint kinase.
    supported_by:
    - reference_id: PMID:11073977
      supporting_text: Inactivation of Mus81 triggers a checkpoint-dependent delay of mitosis.
      reference_section_type: ABSTRACT
- term:
    id: GO:0000709
    label: meiotic joint molecule formation
  evidence_type: TAS
  original_reference_id: PMID:15466419
  qualifier: involved_in
  review:
    summary: |-
      Author-statement annotation derived from the Swi5 meiotic joint-molecule study, which
      describes Mus81-Eme1 as the activity that resolves joint molecules such as Holliday
      junctions. Note that Mus81 acts in the processing/resolution of joint molecules rather
      than in their formation per se; the cited evidence supports resolution. The term as
      annotated (joint molecule formation) is therefore a borderline fit.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited evidence describes Mus81-Eme1 as resolving joint molecules, not forming them; resolution is already captured by GO:0000712.
    supported_by:
    - reference_id: PMID:15466419
      supporting_text: the swi5 deletion strongly suppressed the low viable spore yield of mutants lacking Mus81*Eme1, which resolves joint molecules such as Holliday junctions.
      reference_section_type: ABSTRACT
- term:
    id: GO:0006301
    label: DNA damage tolerance
  evidence_type: TAS
  original_reference_id: PMID:14993467
  qualifier: involved_in
  review:
    summary: |-
      Author-statement annotation: Mus81-Eme1 functions in a sub-pathway of post-replication
      repair for the tolerance/repair of UV-induced DNA damage, together with the Srs2 helicase.
      Consistent with Mus81's broader characterization as a damage-tolerance protein.
    action: ACCEPT
    reason: Supported by epistasis analysis placing Mus81-Eme1 in a PRR/damage-tolerance sub-pathway.
    supported_by:
    - reference_id: PMID:14993467
      supporting_text: Srs2 and the structure-specific endonuclease Mus81-Eme1 function in a sub-pathway of PRR for the tolerance/repair of UV-induced damage.
      reference_section_type: ABSTRACT
- term:
    id: GO:0007131
    label: reciprocal meiotic recombination
  evidence_type: IMP
  original_reference_id: PMID:14704204
  qualifier: involved_in
  review:
    summary: |-
      Mutant-phenotype evidence that Mus81 is required for meiotic crossing over: mus81 mutants
      show normal/elevated gene conversion but 20-100-fold reduced crossover frequencies,
      genetically separating crossing over from gene conversion and establishing Mus81 as the
      meiotic crossover (reciprocal recombination) resolvase in S. pombe. Core meiotic function.
    action: ACCEPT
    reason: Core meiotic crossover role directly demonstrated by mutant crossover/gene-conversion analysis.
    supported_by:
    - reference_id: PMID:14704204
      supporting_text: Schizosaccharomyces pombe mus81 mutants have normal or elevated frequencies of gene conversion but 20- to 100-fold reduced frequencies of crossing over.
      reference_section_type: ABSTRACT
- term:
    id: GO:0008821
    label: crossover junction DNA endonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:11741546
  qualifier: enables
  review:
    summary: |-
      Direct biochemical evidence (from the human Mus81 ortholog) that Mus81-associated
      endonuclease cleaves Holliday junctions in vitro, resolving them into linear duplexes by
      cutting strands of like polarity. Supports the conserved crossover junction endonuclease
      activity assigned to fission yeast Mus81. Although the assay was on human Mus81, the
      activity is conserved and directly characterized for S. pombe Mus81-Eme1 in companion
      studies (PMID:11719193, PMID:14527419, PMID:17363897).
    action: ACCEPT
    reason: Core molecular function; conserved HJ-cleavage activity directly demonstrated, with concordant S. pombe data.
    supported_by:
    - reference_id: PMID:11741546
      supporting_text: Mus81-associated endonuclease resolves Holliday junctions into linear duplexes by cutting across the junction exclusively on strands of like polarity.
      reference_section_type: ABSTRACT
- term:
    id: GO:0048476
    label: Holliday junction resolvase complex
  evidence_type: IDA
  original_reference_id: PMID:14527419
  qualifier: part_of
  review:
    summary: |-
      Direct evidence that the endogenous Mus81-Eme1 complex resolves Holliday junctions by a
      nick-and-counternick mechanism, confirming Mus81 as part of the resolvase complex and
      defining its mechanism (cleavage opposite the nick on a nicked HJ, its preferred
      substrate). Core cellular component and mechanism.
    action: ACCEPT
    reason: Core CC directly demonstrated; the endogenous complex resolves HJs.
    supported_by:
    - reference_id: PMID:14527419
      supporting_text: Mus81-Eme1 resolves HJs by a nick and counternick mechanism, with a large rate enhancement of the second cut arising from the flexible nature of the nicked HJ intermediate.
      reference_section_type: ABSTRACT
core_functions:
- description: >-
    Structure-specific (branched-DNA) endonuclease activity as the catalytic subunit of the
    Mus81-Eme1 complex, cleaving nicked Holliday junctions, 3'-flaps, D-loops, replication forks
    and intact Holliday junctions.
  supported_by:
  - reference_id: PMID:11719193
    supporting_text: We report that Mus81 and an associated protein Eme1 are components of an endonuclease that resolves Holliday junctions into linear duplex products.
    reference_section_type: ABSTRACT
  - reference_id: PMID:14527419
    supporting_text: a nicked HJ is the preferred substrate of endogenous and recombinant Mus81-Eme1
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0008821
    label: crossover junction DNA endonuclease activity
  in_complex:
    id: GO:0048476
    label: Holliday junction resolvase complex
  directly_involved_in:
  - id: GO:0000712
    label: resolution of meiotic recombination intermediates
- description: >-
    Resolution of meiotic recombination intermediates to generate reciprocal crossovers; in S.
    pombe Mus81-Eme1 is the principal/essential meiotic crossover resolvase, with most or all
    crossovers depending on it.
  supported_by:
  - reference_id: PMID:14704204
    supporting_text: Mus81 is required for crossing over, supporting the hypothesis that the fission yeast Mus81.Eme1 protein complex resolves Holliday junctions in meiotic cells.
    reference_section_type: ABSTRACT
  - reference_id: PMID:17363897
    supporting_text: in the fission yeast Schizosaccharomyces pombe most, if not all, COs depend on Mus81
    reference_section_type: INTRODUCTION
  directly_involved_in:
  - id: GO:0007131
    label: reciprocal meiotic recombination
- description: >-
    Processing of stalled and collapsed replication forks and repair of replication-associated
    DNA double-strand breaks via homologous recombination, cleaving fork-derived branched
    intermediates.
  supported_by:
  - reference_id: PMID:28586299
    supporting_text: loss of mus81 causes a > 2 fold reduction in SDDs in strains with either a 2 or 5 kb centromere-proximal spacer DNA (Figure 4B), indicating that Mus81-Eme1 specifically promotes SDDs.
    reference_section_type: RESULTS
  - reference_id: PMID:17307401
    supporting_text: In Deltamus7 and Deltamus81 cells, the repair of MMS-induced DNA double-strand breaks (DSBs) is severely impaired.
    reference_section_type: ABSTRACT
  directly_involved_in:
  - id: GO:0031297
    label: replication fork processing
- description: >-
    Contribution to the replication checkpoint / S-phase DNA damage checkpoint, interacting with
    and being regulated by the Cds1 (Chk2) kinase to restrain inappropriate recombination during
    replication stress.
  supported_by:
  - reference_id: PMID:11073977
    supporting_text: the forkhead-associated-1 (FHA1) protein-docking domain of Cds1 interacts with Mus81, an evolutionarily conserved damage tolerance protein.
    reference_section_type: ABSTRACT
  - reference_id: PMID:19037101
    supporting_text: We have identified proteins downstream of Cds1 required for checkpoint-dependant slowing, including the structure-specific endonuclease Mus81 and the helicase Rqh1
    reference_section_type: ABSTRACT
  directly_involved_in:
  - id: GO:0031573
    label: mitotic intra-S DNA damage checkpoint signaling
proposed_new_terms: []
suggested_questions:
- question: >-
    Does Mus81 have any genuine function at the mitochondrial DNA, or is the reported
    mitochondrial localization a high-throughput artifact?
  experts: []
- question: >-
    How is the switch between Mus81-Eme1's nicked-HJ activity (heterodimer) and intact-HJ backup
    activity (dimer of heterodimers) controlled in vivo during meiosis and fork repair?
  experts: []
- question: >-
    What is the precise role of Cds1-dependent phosphorylation (e.g. Thr275) in regulating Mus81
    chromatin association and timing of fork cleavage during replication stress?
  experts: []
suggested_experiments:
- description: >-
    Test for any mitochondrial role of Mus81 by assaying mtDNA integrity, point-mutation/deletion
    rates, and petite formation in mus81-delta versus wild-type, and confirm/refute mitochondrial
    localization by fractionation and high-resolution imaging of endogenously tagged Mus81.
- description: >-
    Use separation-of-function and phospho-mutant alleles (e.g. catalytic DD->AA, T275A) combined
    with ChIP and physical analysis of recombination/replication intermediates to dissect the
    cell-cycle and checkpoint regulation of Mus81-Eme1 activity at stalled forks.
- description: >-
    Reconstitute meiotic crossover resolution in vitro and in vivo to determine whether the
    intact-HJ "backup" cleavage activity of Mus81-Eme1 contributes measurably to crossover/
    non-crossover outcomes in S. pombe meiosis.
references:
- id: file:interpro/panther/PTHR13451/PTHR13451-review.md
  title: 'PANTHER family review PTHR13451: IBA propagation assessment for mus81'
  findings: []
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000111
  title: Gene Ontology annotations Inferred by Curator (IC) using at least one Inferred by Sequence Similarity (ISS) annotation to support the inference
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11073977
  title: Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1.
  findings:
  - statement: >-
      The FHA1 domain of the replication checkpoint kinase Cds1 interacts with Mus81, and
      inactivation of mus81 triggers a checkpoint-dependent delay of mitosis, implicating Mus81
      in the replication-stress checkpoint and damage tolerance.
    supporting_text: the forkhead-associated-1 (FHA1) protein-docking domain of Cds1 interacts with Mus81, an evolutionarily conserved damage tolerance protein.
    reference_section_type: ABSTRACT
- id: PMID:11719193
  title: Mus81-Eme1 are essential components of a Holliday junction resolvase.
  findings:
  - statement: >-
      Mus81 and Eme1 form a nuclear endonuclease that resolves Holliday junctions into linear
      duplex products and is required at a late step of meiotic recombination; the meiotic defect
      is rescued by a bacterial HJ resolvase.
    supporting_text: We report that Mus81 and an associated protein Eme1 are components of an endonuclease that resolves Holliday junctions into linear duplex products.
    reference_section_type: ABSTRACT
- id: PMID:11741546
  title: Human Mus81-associated endonuclease cleaves Holliday junctions in vitro.
  findings:
  - statement: >-
      The conserved Mus81-associated endonuclease cleaves Holliday junctions in vitro, resolving
      them into linear duplexes by cutting strands of like polarity.
    supporting_text: Mus81-associated endonuclease resolves Holliday junctions into linear duplexes by cutting across the junction exclusively on strands of like polarity.
    reference_section_type: ABSTRACT
- id: PMID:14527419
  title: The endogenous Mus81-Eme1 complex resolves Holliday junctions by a nick and counternick mechanism.
  findings:
  - statement: >-
      The nicked Holliday junction is the preferred substrate of endogenous Mus81-Eme1, which
      resolves HJs by a nick-and-counternick mechanism; HJs accumulate in a pol-alpha mutant
      lacking Mus81.
    supporting_text: a nicked HJ is the preferred substrate of endogenous and recombinant Mus81-Eme1.
    reference_section_type: ABSTRACT
- id: PMID:14704204
  title: Fission yeast Mus81.Eme1 Holliday junction resolvase is required for meiotic crossing over but not for gene conversion.
  findings:
  - statement: >-
      mus81 mutants have normal/elevated gene conversion but 20-100-fold reduced crossing over,
      genetically separating the two and establishing Mus81 as required for meiotic crossovers.
    supporting_text: Schizosaccharomyces pombe mus81 mutants have normal or elevated frequencies of gene conversion but 20- to 100-fold reduced frequencies of crossing over.
    reference_section_type: ABSTRACT
- id: PMID:14993467
  title: The involvement of Srs2 in post-replication repair and homologous recombination in fission yeast.
  findings:
  - statement: >-
      Mus81-Eme1 and Srs2 act in a post-replication-repair sub-pathway for tolerance/repair of
      UV-induced DNA damage.
    supporting_text: Srs2 and the structure-specific endonuclease Mus81-Eme1 function in a sub-pathway of PRR for the tolerance/repair of UV-induced damage.
    reference_section_type: ABSTRACT
- id: PMID:15466419
  title: Swi5 acts in meiotic DNA joint molecule formation in Schizosaccharomyces pombe.
  findings:
  - statement: >-
      Mus81-Eme1 resolves joint molecules such as Holliday junctions; swi5 deletion suppresses
      the low spore viability of Mus81-Eme1 mutants, situating Mus81 in joint-molecule processing.
    supporting_text: the swi5 deletion strongly suppressed the low viable spore yield of mutants lacking Mus81*Eme1, which resolves joint molecules such as Holliday junctions.
    reference_section_type: ABSTRACT
- id: PMID:16823372
  title: ORFeome cloning and global analysis of protein localization in the fission yeast Schizosaccharomyces pombe.
  findings:
  - statement: >-
      Genome-wide YFP localization study; source of the high-throughput nuclear and (uncorroborated)
      mitochondrial localization calls for Mus81.
    supporting_text: we determined the localization of 4,431 proteins, corresponding to approximately 90% of the fission yeast proteome, by tagging each ORF with the yellow fluorescent protein.
    reference_section_type: ABSTRACT
- id: PMID:17307401
  title: The novel gene mus7(+) is involved in the repair of replication-associated DNA damage in fission yeast.
  findings:
  - statement: >-
      Mus7 acts in the same pathway as Mus81; mus81 (and mus7) deletion severely impairs repair
      of MMS-induced DSBs, implicating Mus81 in repair of replication-associated DNA damage.
    supporting_text: In Deltamus7 and Deltamus81 cells, the repair of MMS-induced DNA double-strand breaks (DSBs) is severely impaired.
    reference_section_type: ABSTRACT
- id: PMID:17363897
  title: 'Mus81 cleavage of Holliday junctions: a failsafe for processing meiotic recombination intermediates?'
  findings:
  - statement: >-
      Active recombinant S. pombe Mus81-Eme1 robustly cleaves intact Holliday junctions as a
      backup to its primary nicked-HJ activity; in S. pombe most or all crossovers depend on Mus81,
      and it also acts at stalled/broken forks and interstrand crosslinks in mitosis.
    supporting_text: in the fission yeast Schizosaccharomyces pombe most, if not all, COs depend on Mus81
    reference_section_type: INTRODUCTION
- id: PMID:19037101
  title: Mus81, Rhp51(Rad51), and Rqh1 form an epistatic pathway required for the S-phase DNA damage checkpoint.
  findings:
  - statement: >-
      Mus81 acts downstream of Cds1 in checkpoint-dependent replication slowing, in an epistatic
      pathway with Rhp51 and Rqh1, contributing to the S-phase DNA damage checkpoint.
    supporting_text: defining an epistatic pathway in which mus81 is epistatic to rhp51 and rhp51 is epistatic to rqh1.
    reference_section_type: ABSTRACT
- id: PMID:25414342
  title: Rad51/Dmc1 paralogs and mediators oppose DNA helicases to limit hybrid DNA formation and promote crossovers during meiotic recombination.
  findings:
  - statement: >-
      Rad51/Dmc1 paralog/mediator complexes (incl. Swi5-Sfr1) antagonize the Fml1 and Rqh1
      helicases to promote Mus81-Eme1-dependent meiotic crossovers.
    supporting_text: play a major role in antagonizing both the FANCM-family DNA helicase/translocase Fml1 and the RecQ-type DNA helicase Rqh1 to limit hybrid DNA formation and promote Mus81-Eme1-dependent COs.
    reference_section_type: ABSTRACT
- id: PMID:28586299
  title: Inter-Fork Strand Annealing causes genomic deletions during the termination of DNA replication.
  findings:
  - statement: >-
      Mus81-Eme1 cleaves stalled forks and recombination intermediates and is required for the
      spacer-dependent deletions formed during inter-fork strand annealing at replication
      termination; recombinant Mus81-Eme1 (but not a catalytic-dead mutant) resolves a model
      IFSA junction in vitro.
    supporting_text: loss of mus81 causes a > 2 fold reduction in SDDs in strains with either a 2 or 5 kb centromere-proximal spacer DNA (Figure 4B), indicating that Mus81-Eme1 specifically promotes SDDs.
    reference_section_type: RESULTS