title: Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response.
abstract: The MUS81 protein belongs to a conserved family of DNA structure-specific nucleases that play important roles in DNA replication and repair. Inactivation of the Mus81 gene in mice has no major deleterious consequences for embryonic development, although cancer susceptibility has been reported. We have investigated the role of MUS81 in human cells by acutely depleting the protein using shRNAs. We found that MUS81 depletion from human fibroblasts leads to accumulation of ssDNA and a constitutive DNA damage response that ultimately activates cellular senescence. Moreover, we show that MUS81 is required for efficient replication fork progression during an unperturbed S-phase, and for recovery of productive replication following replication stalling. These results demonstrate essential roles for the MUS81 nuclease in maintenance of replication fork integrity.
authors.affiliation: Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Meichun
authors.initials: M
authors.lastname: Xing
authors.affiliation: Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Life Sciences, University of Lincoln, Lincoln, United Kingdom.
authors.forename: Timea
authors.initials: T
authors.lastname: Palmai-Pallag
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Institute of Respiratory Diseases, Zhejiang University School of Medicine, Hangzhou, China.|State Key Laboratory For Respiratory Diseases, Guangzhou, China.
authors.forename: Huahao
authors.initials: H
authors.lastname: Shen
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.affiliation: Center for Chromosome Stability and Nordea Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Hickson
authors.affiliation: Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.|Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Institute of Respiratory Diseases, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Songmin
authors.initials: S
authors.lastname: Ying
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D004720:Endonucleases; C498772:MUS81 protein, human
keywords: DNA replication; Holliday junctions; NBS1; cellular senescence; homologous recombination