Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response

Xing, Meichun and Wang, Xiaohui and Palmai-Pallag, Timea and Shen, Huahao and Helleday, Thomas and Hickson, Ian D. and Ying, Songmin (2015) Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response. Oncotarget, 6 (35). pp. 37638-37646. ISSN 1949-2553

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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.

Keywords:cellular senescence, DNA replication, Holliday junctions, homologous recombination, NBS1, JCOpen
Subjects:C Biological Sciences > C440 Molecular Genetics
C Biological Sciences > C420 Human Genetics
C Biological Sciences > C130 Cell Biology
C Biological Sciences > C790 Molecular Biology, Biophysics and Biochemistry not elsewhere classified
Divisions:College of Science > School of Life Sciences
ID Code:18921
Deposited On:07 Oct 2015 10:37

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