期刊
EMBO JOURNAL
卷 28, 期 23, 页码 3667-3680出版社
WILEY
DOI: 10.1038/emboj.2009.302
关键词
camptothecin; DNA repair; gamma H2AX; Topoisomerase 1; XRCC1
资金
- NCI Intramural Program
- Center for Cancer Research
- National Cancer Institute
- NIH
- A-T Medical Research Foundation
- Israel Cancer Research Fund
Human tyrosyl-DNA phosphodiesterase (TDP1) hydrolyzes the phosphodiester bond at a DNA 3' end linked to a tyrosyl moiety. This type of linkage is found at stalled topoisomerase I (Top1)-DNA covalent complexes, and TDP1 has been implicated in the repair of such complexes. Here we show that Top1-associated DNA double-stranded breaks (DSBs) induce the phosphorylation of TDP1 at S81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (ATM) and DNA-dependent protein kinase (DNA-PK). Phosphorylated TDP1 forms nuclear foci that co-localize with those of phosphorylated histone H2AX (gamma H2AX). Both Top1-induced replication-and transcription-mediated DNA damages induce TDP1 phosphorylation. Furthermore, we show that S81 phosphorylation stabilizes TDP1, induces the formation of XRCC1 (X-ray cross-complementing group 1)-TDP1 complexes and enhances the mobilization of TDP1 to DNA damage sites. Finally, we provide evidence that TDP1-S81 phosphorylation promotes cell survival and DNA repair in response to CPT-induced DSBs. Together; our findings provide a new mechanism for TDP1 post-translational regulation by ATM and DNA-PK. The EMBO Journal (2009) 28, 3667-3680. doi: 10.1038/emboj.2009.302; Published online 22 October 2009
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据