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CtIP 与 BRCA1 之间的相互作用对于切除介导的 DNA 修复或肿瘤抑制并非必需。

The interaction between CtIP and BRCA1 is not essential for resection-mediated DNA repair or tumor suppression.

机构信息

Institute for Cancer Genetics, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.

出版信息

J Cell Biol. 2013 May 27;201(5):693-707. doi: 10.1083/jcb.201302145.

DOI:10.1083/jcb.201302145
PMID:23712259
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3664708/
Abstract

The CtIP protein facilitates homology-directed repair (HDR) of double-strand DNA breaks (DSBs) by initiating DNA resection, a process in which DSB ends are converted into 3'-ssDNA overhangs. The BRCA1 tumor suppressor, which interacts with CtIP in a phospho-dependent manner, has also been implicated in DSB repair through the HDR pathway. It was recently reported that the BRCA1-CtIP interaction is essential for HDR in chicken DT40 cells. To examine the role of this interaction in mammalian cells, we generated cells and mice that express Ctip polypeptides (Ctip-S326A) that fail to bind BRCA1. Surprisingly, isogenic lines of Ctip-S326A mutant and wild-type cells displayed comparable levels of HDR function and chromosomal stability. Although Ctip-S326A mutant cells were modestly sensitive to topoisomerase inhibitors, mice expressing Ctip-S326A polypeptides developed normally and did not exhibit a predisposition to cancer. Thus, in mammals, the phospho-dependent BRCA1-CtIP interaction is not essential for HDR-mediated DSB repair or for tumor suppression.

摘要

CtIP 蛋白通过启动 DNA 切除来促进双链 DNA 断裂 (DSB) 的同源定向修复 (HDR)，这是一个将 DSB 末端转化为 3'-ssDNA 突出端的过程。BRCA1 肿瘤抑制因子与 CtIP 以磷酸化依赖的方式相互作用，也被牵连到 HDR 途径中的 DSB 修复中。最近有报道称，BRCA1-CtIP 相互作用对于鸡 DT40 细胞中的 HDR 至关重要。为了研究这种相互作用在哺乳动物细胞中的作用，我们生成了表达不能结合 BRCA1 的 Ctip 多肽 (Ctip-S326A) 的细胞和小鼠。令人惊讶的是，Ctip-S326A 突变体和野生型细胞的同基因系显示出相当水平的 HDR 功能和染色体稳定性。尽管 Ctip-S326A 突变体细胞对拓扑异构酶抑制剂有一定的敏感性，但表达 Ctip-S326A 多肽的小鼠发育正常，没有癌症易感性。因此，在哺乳动物中，磷酸化依赖的 BRCA1-CtIP 相互作用对于 HDR 介导的 DSB 修复或肿瘤抑制并非必不可少。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/2153ac23fde8/JCB_201302145_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/dd5fda5afac3/JCB_201302145_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/bfac896c4783/JCB_201302145_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/045c9e7c46c5/JCB_201302145_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/14aef53917cb/JCB_201302145_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/5836ceaf41cf/JCB_201302145_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/ae533ee6e419/JCB_201302145_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/31082ba935c8/JCB_201302145_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/d694c7dbf406/JCB_201302145_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/2153ac23fde8/JCB_201302145_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/dd5fda5afac3/JCB_201302145_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/bfac896c4783/JCB_201302145_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/045c9e7c46c5/JCB_201302145_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/14aef53917cb/JCB_201302145_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/5836ceaf41cf/JCB_201302145_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/ae533ee6e419/JCB_201302145_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/31082ba935c8/JCB_201302145_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/d694c7dbf406/JCB_201302145_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6629/3664708/2153ac23fde8/JCB_201302145_Fig9.jpg

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