生物
DNA损伤
细胞生物学
DNA修复
G2-M DNA损伤检查点
基因组不稳定性
分子生物学
DNA
遗传学
基因
细胞周期检查点
细胞周期
作者
Zhenkun Lou,Katherine Minter-Dykhouse,Sonia Franco,Monica Gostissa,Melissa A. Rivera,Arkady Celeste,John P. Manis,Jan van Deursen,André Nussenzweig,Tanya T. Paull,Frederick W. Alt,Junjie Chen
出处
期刊:Molecular Cell
[Elsevier]
日期:2006-01-01
卷期号:21 (2): 187-200
被引量:567
标识
DOI:10.1016/j.molcel.2005.11.025
摘要
MDC1 functions in checkpoint activation and DNA repair following DNA damage. To address the physiological role of MDC1, we disrupted the MDC1 gene in mice. MDC1−/− mice recapitulated many phenotypes of H2AX−/− mice, including growth retardation, male infertility, immune defects, chromosome instability, DNA repair defects, and radiation sensitivity. At the molecular level, H2AX, MDC1, and ATM form a positive feedback loop, with MDC1 directly mediating the interaction between H2AX and ATM. MDC1 binds phosphorylated H2AX through its BRCT domain and ATM through its FHA domain. Through these interactions, MDC1 accumulates activated ATM flanking the sites of DNA damage, facilitating further ATM-dependent phosphorylation of H2AX and the amplification of DNA damage signals. In the absence of MDC1, many downstream ATM signaling events are defective. These results suggest that MDC1, as a signal amplifier of the ATM pathway, is vital in controlling proper DNA damage response and maintaining genomic stability.
科研通智能强力驱动
Strongly Powered by AbleSci AI