Chk1 and Chk2 are differentially involved in homologous recombination repair and cell cycle arrest in response to DNA double-strand breaks induced by camptothecins

doi:10.1158/1535-7163.MCT-07-2116

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	Chk1 and Chk2 are differentially involved in homologous recombination repair and cell cycle arrest in response to DNA double-strand breaks induced by camptothecins
	Huang, Min1 ; Miao, Ze-Hong 1; Zhu, Hong 1; Cai, Yu-Jun 1; Lu, Wei 2; Ding, Jian1
刊名	MOLECULAR CANCER THERAPEUTICS
	2008-06
卷号	7 期号:6 页码:1440-1449
ISSN号	1535-7163
DOI	10.1158/1535-7163.MCT-07-2116
文献子类	Article
英文摘要	Camptothecins (CPT) activate S or G(2)-M arrest and the homologous recombination (HR) repair pathway in tumor cells. In this process, both checkpoint kinases 1 and 2 (Chk1 and Chk2, respectively) are activated, but their differential roles, especially in the coordination of checkpoint and repair control, and potential clinic relevance remain to be fully elucidated. In this study, the repairable double-strand breaks were induced in human colon cancer HCT116 cells by 1-h exposure to 25 or 100 nmol/L CPT and its novel derivative chimmitecan. The cellular disposal of double-strand breaks was reflected as the progressive dispersal of gamma-H2AX foci, reduction of "comet" tails, dynamic activation of RAD51-mediated HR repair, and reversible G(2)-M arrest. In this model, the differential kinetics of Chk1 and Chk2 activation was characterized by the progressively increased phosphorylation of Chk2 until 72 h, the degradation of Chk1, and the disappearance of phosphorylated Chk1 48 h after drug removal. Using RNA interference, we further showed that Chk2 was essential to G(2)-M arrest, whereas Chk1 was mainly required for HR repair in CPT-treated HCT116 cells. Moreover, Chk2, rather than Chk1, predominated over the control of cell survival in this model. The differential roles of Chk1 and Chk2 in regulating HR repair and G(2)-M phase arrest were also confirmed in HT-29 colon cancer cells. Together, these findings systematically dissect the differential roles of Chk1 and Chk2 in a favorable model pursuing CPT-driven DNA damage responses, providing critical evidence to further explore checkpoint modulation, especially Chk2 inhibition as a therapeutic strategy in combination with CPT.
WOS关键词	CHECKPOINT KINASE CHK2 ; TOPOISOMERASE-I ; MITOTIC CATASTROPHE ; IONIZING-RADIATION ; PROTEIN-KINASE ; DAMAGE ; PHOSPHORYLATION ; CANCER ; ATM ; DEGRADATION
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000256955900011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272911]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Ding, Jian
作者单位	1.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Div Chem, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Huang, Min,Miao, Ze-Hong,Zhu, Hong,et al. Chk1 and Chk2 are differentially involved in homologous recombination repair and cell cycle arrest in response to DNA double-strand breaks induced by camptothecins[J]. MOLECULAR CANCER THERAPEUTICS,2008,7(6):1440-1449.
APA	Huang, Min,Miao, Ze-Hong,Zhu, Hong,Cai, Yu-Jun,Lu, Wei,&Ding, Jian.(2008).Chk1 and Chk2 are differentially involved in homologous recombination repair and cell cycle arrest in response to DNA double-strand breaks induced by camptothecins.MOLECULAR CANCER THERAPEUTICS,7(6),1440-1449.
MLA	Huang, Min,et al."Chk1 and Chk2 are differentially involved in homologous recombination repair and cell cycle arrest in response to DNA double-strand breaks induced by camptothecins".MOLECULAR CANCER THERAPEUTICS 7.6(2008):1440-1449.