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WRN缺陷细胞中的复制叉停滞可通过迅速激活MUS81依赖的途径来克服。

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

作者信息

Franchitto Annapaola, Pirzio Livia Maria, Prosperi Ennio, Sapora Orazio, Bignami Margherita, Pichierri Pietro

机构信息

Section of Experimental and Computational Carcinogenesis, Istituto Superiore di Sanità, 00161 Rome, Italy.

出版信息

J Cell Biol. 2008 Oct 20;183(2):241-52. doi: 10.1083/jcb.200803173. Epub 2008 Oct 13.

DOI:10.1083/jcb.200803173
PMID:18852298
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2568021/
Abstract

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.

摘要

无法稳定并正确处理停滞的复制叉会导致染色体不稳定，这是癌细胞和几种以癌症易感性为特征的人类遗传疾病的一个标志。WRN是一种在易患癌症的沃纳综合征（WS）中发生突变的类RecQ酶，其缺失会导致双链断裂（DSB）迅速积累，并且在DNA复制停滞时增殖细胞核抗原从染色质上移除。在WRN缺陷细胞中敲低MUS81核酸内切酶可完全防止复制叉停滞后DSB的积累。此外，在WS细胞中敲低MUS81会导致重组酶在染色质上的募集减少、姐妹染色单体交换产量降低以及复制停滞后的存活率降低。因此，我们提供了新的证据，表明WRN是避免复制扰动后DSB积累和复制叉崩溃所必需的，并且在这种病理条件下，由MUS81迅速依赖性产生的DSB有助于从羟基脲介导的复制停滞中恢复。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/bfeab955d4f6/jcb1830241f07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/ab14ad3bcef1/jcb1830241f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/b06191ff103e/jcb1830241f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/180be046d97f/jcb1830241f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/a82aaf46bdea/jcb1830241f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/c23d42cb1ddb/jcb1830241f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/84a4080e19ee/jcb1830241f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/bfeab955d4f6/jcb1830241f07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/ab14ad3bcef1/jcb1830241f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/b06191ff103e/jcb1830241f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/180be046d97f/jcb1830241f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/a82aaf46bdea/jcb1830241f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/c23d42cb1ddb/jcb1830241f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/84a4080e19ee/jcb1830241f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eff6/2568021/bfeab955d4f6/jcb1830241f07.jpg

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