Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response
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Meichun Xing1, Xiaohui Wang1, Timea Palmai-Pallag2, Huahao Shen3,4, Thomas Helleday5, Ian D. Hickson6, Songmin Ying1,3
1Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China
2School of Life Sciences, University of Lincoln, Lincoln, United Kingdom
3Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Institute of Respiratory Diseases, Zhejiang University School of Medicine, Hangzhou, China
4State Key Laboratory For Respiratory Diseases, Guangzhou, China
5Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
6Center for Chromosome Stability and Nordea Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
Songmin Ying, e-mail: [email protected]
Keywords: cellular senescence, DNA replication, Holliday junctions, homologous recombination, NBS1
Received: June 28, 2015 Accepted: September 11, 2015 Published: September 22, 2015
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.
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