Alternative titles; symbols
HGNC Approved Gene Symbol: MUS81
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38) : 11:65,859,674-65,867,653 (from NCBI)
MUS81 is a member of the XPF (ERCC4; 133520) family of endonucleases that forms a complex with EME1 (610885). The MUS81-EME1 complex cleaves DNA structures at stalled replication forks that are subsequently repaired by homologous recombination (summary by Ho et al., 2016).
By searching for sequences with similarity to S. pombe and S. cerevisiae Mus81, followed by PCR using a cerebellum cDNA library, Chen et al. (2001) cloned the human homolog of yeast Mus81. The open reading frame of human MUS81 predicts a translation product of 551 amino acids with a molecular mass of 59 kD. The predicted protein has 25% identity to Mus81 of fission yeast. Sequence alignment of the human, mouse, fission yeast, and budding yeast proteins revealed that the similarity is highest around the VERKX3D motif, which is conserved in the XPF family of nucleases. Helix-hairpin-helix DNA-binding domains in the N and C termini of the protein also appeared to be conserved. Northern blot analysis showed that MUS81 mRNA was ubiquitously expressed in several human cell types and cell lines.
Chen et al. (2001) mapped the MUS81 gene to chromosome 11q13 by FISH and confirmed the localization by genomic sequence analysis.
Chen et al. (2001) showed that MUS81 has associated endonuclease activity against structure-specific oligonucleotide substrates, including synthetic Holliday junctions. MUS81-associated endonuclease resolved Holliday junctions into linear duplexes by cutting across the junction exclusively on strands of like polarity. In addition, MUS81 protein abundance increased in cells following exposure to agents that block DNA replication. Taken together, these findings suggested a role for MUS81 in resolving Holliday junctions that arise when DNA replication is blocked by damage or by nucleotide depletion. The authors stated that MUS81 is not related by sequence to previously characterized Holliday junction-resolving enzymes, and it has distinct enzymatic properties that suggest it uses a novel enzymatic strategy to cleave Holliday junctions.
Ciccia et al. (2003) showed that recombinant MUS81 interacted with recombinant EME1 and EME2 (610886). EME1/MUS81 heterodimers showed DNA endonuclease activity against 3-prime flap and replication fork substrates, but activity was much lower against splayed arm and Holliday junction substrates. Neither EME1 nor MUS81 alone showed nuclease activity.
Ciccia et al. (2007) found that the EME2/MUS81 heterodimer exhibited DNA endonuclease activity against 3-prime flap and splayed arm substrates.
Zeng et al. (2009) showed that MUS81 contributes to the alternative lengthening of telomeres (ALT) pathway for maintenance of telomere length in telomerase-negative human cancer cell lines that utilized the ALT pathway. In ALT cells only, MUS81 localized to PML (102578)-positive nuclear bodies and with telomeric DNA, which was enriched during the G2 phase of the cell cycle in synchronized ALT cells. Depletion of MUS81 via short hairpin RNA in ALT cells resulted in reduced ALT-specific recombination, defective S phase and proliferation, and loss of telomere signals. MUS81 did not participate in global telomere maintenance in non-ALT cell lines. Mutation analysis showed that the endonuclease activity of MUS81 was required for recombination-based ALT cell survival. Coimmunoprecipitation analysis and mass spectrometry revealed that MUS81 interacted with TRF2 (TERF2; 602027) as well as EME1. The interaction of MUS81 with TRF2 inhibited the nuclease activity of MUS81; chromatin immunoprecipitation analysis showed that the binding of MUS81 to TRF2 interfered with the binding of MUS81 to DNA. Zeng et al. (2009) concluded that MUS81 is involved in the maintenance of ALT cell survival at least in part by homologous recombination of telomeres.
Wechsler et al. (2011) used Bloom syndrome (210900) cells, in which the BLM gene (604610) is inactive, to analyze human cells compromised for the known Holliday junction dissolution/resolution pathways. Wechsler et al. (2011) showed that depletion of MUS81 and GEN1 (612449), or SLX4 (613278) and GEN1, from Bloom syndrome cells results in severe chromosome abnormalities, such that sister chromatids remain interlinked in a side-by-side arrangement and the chromosomes are elongated and segmented. Wechsler et al. (2011) concluded that normally replicating human cells require Holliday junction processing activities to prevent sister chromatid entanglements and thereby ensure accurate chromosome condensation. This phenotype was not apparent when both MUS81 and SLX4 were depleted from Bloom syndrome cells, suggesting that GEN1 can compensate for their absence. Additionally, Wechsler et al. (2011) showed that depletion of MUS81 or SLX4 reduces the high frequency of sister chromatid exchanges in Bloom syndrome cells, indicating that MUS81 and SLX4 promote sister chromatid exchange formation, in events that may ultimately drive the chromosome instabilities that underpin early-onset cancers associated with Bloom syndrome.
Mayle et al. (2015) showed that broken fork repair initially uses error-prone Pol32 (see POLD3, 611415)-dependent synthesis, but that mutagenic synthesis is limited to within a few kilobases from the break by Mus81 endonuclease and a converging fork. Mus81 suppresses template switches between both homologous sequences and diverged human Alu repetitive elements, highlighting its importance for stability of highly repetitive genomes. Mayle et al. (2015) proposed that lack of a timely converging fork or Mus81 may propel genome instability observed in cancer.
By immunohistochemical analysis, Ho et al. (2016) showed that mouse and human prostate cancer cell lines shed genomic DNA into the cytosol. Shedding could be prevented by inhibiting MUS81. Nuclear MUS81 foci were elevated in most cancer tissues, but not in healthy tissues from the same patients. MUS81 foci and cytosolic double-stranded DNA increased from hyperplasia to clinical stage II prostate cancer, and then decreased in stage III. Overexpression of Mus81 in mouse embryonic fibroblasts and mouse and human prostate cancer cells increased phosphorylation of IRF3 (603734) and expression of IRF3 target genes. Increased cytosolic DNA increased IFNB (147640) expression. Expression of type I interferon depended on the presence of STING (TMEM173; 612374) in prostate cancer cells. Mus81 and Sting contributed to type I interferon- and T cell-dependent rejection of prostate cancer cells in mice. Ho et al. (2016) concluded that MUS81 enhances innate and adaptive anticancer immune responses.
The MUS81-EME1 structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at common fragile sites (CFSs) following replicative stress. Minocherhomji et al. (2015) showed that entry of cells into mitotic prophase triggers the recruitment of MUS81 to CFSs. The nuclease activity of MUS81 then promotes POLD3-dependent DNA synthesis at CFSs, which serves to minimize chromosome missegregation and nondisjunction. Minocherhomji et al. (2015) proposed that the attempted condensation of incompletely duplicated loci in early mitosis serves as the trigger for completion of DNA replication at CFS loci in human cells. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability (CIN+) and replicative stress, the authors suggested that targeting this pathway could represent a novel therapeutic approach.
McPherson et al. (2004) used gene targeting to study the physiologic requirements of Mus81 in mammals. Mus81-null mice were viable and fertile, which indicates that mammalian Mus81 is not essential for recombination processes associated with meiosis. Mus81-deficient mice and cells were hypersensitive to the DNA crosslinking agent mitomycin C but not to gamma-irradiation. Remarkably, both homozygous Mus81-null mice and heterozygous Mus81 +/- mice exhibited a similar susceptibility to spontaneous chromosomal damage and a profound and equivalent predisposition to lymphomas and other cancers. McPherson et al. (2004) concluded that their studies demonstrated a critical role for the proper biallelic expression of the mammalian Mus81 in the maintenance of genomic integrity and tumor suppression.
Chen, X.-B., Melchionna, R., Denis, C.-M., Gaillard, P.-H. L., Blasina, A., Van de Weyer, I., Boddy, M. N., Russell, P., Vialard, J., McGowan, C. H. Human Mus81-associated endonuclease cleaves Holliday junctions in vitro. Molec. Cell 8: 1117-1127, 2001. [PubMed: 11741546] [Full Text: https://doi.org/10.1016/s1097-2765(01)00375-6]
Ciccia, A., Constantinou, A., West, S. C. Identification and characterization of the human Mus81-Eme1 endonuclease. J. Biol. Chem. 278: 25172-25178, 2003. [PubMed: 12721304] [Full Text: https://doi.org/10.1074/jbc.M302882200]
Ciccia, A., Ling, C., Coulthard, R., Yan, Z., Xue, Y., Meetei, A. R., Laghmani, E. H., Joenje, H., McDonald, N., de Winter, J. P., Wang, W., West, S. C. Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. Molec. Cell 25: 331-343, 2007. [PubMed: 17289582] [Full Text: https://doi.org/10.1016/j.molcel.2007.01.003]
Ho, S. S. W., Zhang, W. Y. L., Tan, N. Y. J., Khatoo, M., Suter, M. A., Tripathi, S., Cheung, F. S. G., Lim, W. K., Tan, P. H., Ngeow, J., Gasser, S. The DNA structure-specific endonuclease MUS81 mediates DNA sensor STING-dependent host rejection of prostate cancer cells. Immunity 44: 1177-1189, 2016. [PubMed: 27178469] [Full Text: https://doi.org/10.1016/j.immuni.2016.04.010]
Mayle, R., Campbell, I. M., Beck, C. R., Yu, Y., Wilson, M., Shaw, C. A., Bjergbaek, L., Lupski, J. R., Ira, G. Mus81 and converging forks limit the mutagenicity of replication fork breakage. Science 349: 742-747, 2015. [PubMed: 26273056] [Full Text: https://doi.org/10.1126/science.aaa8391]
McPherson, J. P., Lemmers, B., Chahwan, R., Pamidi, A., Migon, E., Matysiak-Zablocki, E., Moynahan, M. E., Essers, J., Hanada, K., Poonepalli, A., Sanchez-Sweatman, O., Khokha, R., Kanaar, R., Jasin, M., Hande, M. P., Hakem, R. Involvement of mammalian Mus81 in genome integrity and tumor suppression. Science 304: 1822-1826, 2004. [PubMed: 15205536] [Full Text: https://doi.org/10.1126/science.1094557]
Minocherhomji, S., Ying, S., Bjerregaard, V. A., Bursomanno, S., Aleliunaite, A., Wu, W., Mankouri, H. W., Shen, H., Liu, Y., Hickson, I. D. Replication stress activates DNA repair synthesis in mitosis. Nature 528: 286-290, 2015. [PubMed: 26633632] [Full Text: https://doi.org/10.1038/nature16139]
Wechsler, T., Newman, S., West, S. C. Aberrant chromosome morphology in human cells defective for Holliday junction resolution. Nature 471: 642-646, 2011. [PubMed: 21399624] [Full Text: https://doi.org/10.1038/nature09790]
Zeng, S., Xiang, T., Pandita, T. K., Gonzalez-Suarez, I., Gonzalo, S., Harris, C. C., Yang, Q. Telomere recombination requires the MUS81 endonuclease. Nature Cell Biol. 11: 616-623, 2009. [PubMed: 19363487] [Full Text: https://doi.org/10.1038/ncb1867]