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

Journal of Cell Biology - Tập 183 Số 2 - Trang 241-252 - 2008
Annapaola Franchitto1, Livia Maria Pirzio1, Ennio Prosperi2, O. Sapora1, Margherita Bignami1, Pietro Pichierri1
11Section of Experimental and Computational Carcinogenesis, Istituto Superiore di Sanità, 00161 Rome, Italy
22Istituto di Genetica Molecolare del Consiglio Nazionale delle Ricerche, sez. Istochimica e Citometria, 27100 Pavia, Italy

Tóm tắt

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.

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Thông tin xuất bản

Journal of Cell Biology

Tập 183 Số 2

241-252

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