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Published online
doi:10.1083/jcb.200803173
The Journal of Cell Biology, Vol. 183, No. 2, 241-252
The Rockefeller University Press, 0021-9525 $30.00
© Franchitto et al.
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Article

Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway



Annapaola Franchitto1, Livia Maria Pirzio1, Ennio Prosperi2, Orazio Sapora1, Margherita Bignami1, and Pietro Pichierri1

1 Section of Experimental and Computational Carcinogenesis, Istituto Superiore di Sanità, 00161 Rome, Italy
2 Istituto di Genetica Molecolare del Consiglio Nazionale delle Ricerche, sez. Istochimica e Citometria, 27100 Pavia, Italy

Correspondence to Pietro Pichierri: pietro.pichierri{at}iss.it

Failure to stabilize and properly process stalled replication forks results in chromosome instability, which is a hallmark of cancer cells and several human genetic conditions that are characterized by cancer predisposition. Loss of WRN, a RecQ-like enzyme mutated in the cancer-prone disease Werner syndrome (WS), leads to rapid accumulation of double-strand breaks (DSBs) and proliferating cell nuclear antigen removal from chromatin upon DNA replication arrest. Knockdown of the MUS81 endonuclease in WRN-deficient cells completely prevents the accumulation of DSBs after fork stalling. Also, MUS81 knockdown in WS cells results in reduced chromatin recruitment of recombination enzymes, decreased yield of sister chromatid exchanges, and reduced survival after replication arrest. Thus, we provide novel evidence that WRN is required to avoid accumulation of DSBs and fork collapse after replication perturbation, and that prompt MUS81-dependent generation of DSBs is instrumental for recovery from hydroxyurea-mediated replication arrest under such pathological conditions.

Abbreviations used in this paper: ATR, ataxia telangiectasia and Rad3–related; CENP-F, centromere protein F; CldU, chlorodeoxyuridine; DSB, double-strand break; HJ, Holliday junction; HU, hydroxyurea; IdU, iododeoxyuridine; PCNA, proliferating cell nuclear antigen; PFGE, pulsed-field gel electrophoresis; SCE, sister chromatid exchange; WS, Werner syndrome.

© 2008 Franchitto et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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