Defective Mre11-dependent Activation of Chk2 by Ataxia Telangiectasia Mutated in Colorectal.pdfVIP

下载本文档

3
0
约5.38万字
约 10页
2017-04-13 发布于江苏
举报
版权申诉

Defective Mre11-dependent Activation of Chk2 by Ataxia Telangiectasia Mutated in Colorectal.pdf

1、原创力文档（book118）网站文档一经付费（服务费），不意味着购买了该文档的版权，仅供个人/单位学习、研究之用，不得用于商业用途，未经授权，严禁复制、发行、汇编、翻译或者网络传播等，侵权必究。。
2、本站所有内容均由合作方或网友上传，本站不对文档的完整性、权威性及其观点立场正确性做任何保证或承诺！文档内容仅供研究参考，付费前请自行鉴别。如您付费，意味着您自己接受本站规则且自行承担风险，本站不退款、不进行额外附加服务；查看《如何避免下载的几个坑》。如果您已付费下载过本站文档，您可以点击这里二次下载。
3、如文档侵犯商业秘密、侵犯著作权、侵犯人身权等，请点击“版权申诉”（推荐），也可以打举报电话：400-050-0827(电话支持时间：9:00-18:30)。
4、该文档为VIP文档，如果想要下载，成为VIP会员后，下载免费。
5、成为VIP后，下载本文档将扣除1次下载权益。下载后，不支持退款、换文档。如有疑问请联系我们。
6、成为VIP后，您将拥有八大权益，权益包括：VIP文档下载权益、阅读免打扰、文档格式转换、高级专利检索、专属身份标志、高级客服、多端互通、版权登记。
7、VIP文档为合作方或网友上传，每下载1次，网站将根据用户上传文档的质量评分、类型等，对文档贡献者给予高额补贴、流量扶持。如果你也想贡献VIP文档。上传文档

Defective Mre11-dependent Activation of Chk2 by Ataxia Telangiectasia Mutated in Colorectal

Defective Mre11-dependent Activation of Chk2 by Ataxia Telangiectasia Mutated in Colorectal Carcinoma Cells in Response to Replication-dependent DNA Double Strand Breaks* Received for publication, April 19, 2006, and in revised form, August 10, 2006 Published, JBC Papers in Press, August 10, 2006, DOI 10.1074/jbc.M603747200 Haruyuki Takemura1, V. Ashutosh Rao1, Olivier Sordet1, Takahisa Furuta, Ze-Hong Miao, LingHua Meng, Hongliang Zhang, and Yves Pommier2 From the Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-4255 The Mre11Rad50Nbs1 (MRN) complex binds DNA dou- ble strand breaks to repair DNA and activate checkpoints.We report MRN deficiency in three of seven colon carcinoma cell lines of the NCI Anticancer Drug Screen. To study the involvement of MRN in replication-mediated DNA double strand breaks, we examined checkpoint responses to campto- thecin, which induces replication-mediated DNA double strand breaks after replication forks collide with topoisomer- ase I cleavage complexes. MRN-deficient cells were deficient for Chk2 activation, whereas Chk1 activation was independ- ent of MRN. Chk2 activation was ataxia telangiectasia mutated (ATM)-dependent and associated with phosphoryl- ation of Mre11 and Nbs1. Mre11 complementation in MRN- deficient HCT116 cells restored Chk2 activation as well as Rad50 and Nbs1 levels. Conversely, Mre11 down-regulation by small interference RNA (siRNA) in HT29 cells inhibited Chk2 activation and down-regulated Nbs1 and Rad50. Pro- teasome inhibition also restored Rad50 and Nbs1 levels in HCT116 cells suggesting that Mre11 stabilizes Rad50 and Nbs1. Chk2 activation was also defective in three of four MRN-proficient colorectal cell lines because of low Chk2 lev- els. Thus, six of seven colon carcinoma cell lines from the NCI Anticancer Drug Screen are functionally Chk2-deficient in response to replication-mediate