Formation of dynamic gamma-H2AX domains along broken DNA strands is distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in chromatin.
Formation of dynamic gamma-H2AX domains along broken DNA strands is distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in chromatin.
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DOI：
10.1016/j.molcel.2009.04.012
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发表时间：
2009-05-15
期刊：
影响因子：
16
通讯作者：
Bassing, Craig H.
中科院分区：
文献类型：
--
作者：
Savic, Velibor;Yin, Bu;Maas, Nancy L.;Bredemeyer, Andrea L.;Carpenter, Andrea C.;Helmink, Beth A.;Yang-lott, Katherine S.;Sleckman, Barry P.;Bassing, Craig H.
细胞对DNA双链断裂（DSBs）反应的一个标志是染色质中组蛋白H2AX磷酸化产生γ-H2AX。在这里，我们证明了γ-H2AX密度随着DNA链在G1期细胞中断裂和修复而瞬间增加。随着dsb的持续存在，γ-H2AX形成的区域不会扩散，而是在距离DNA末端固定距离内，γ-H2AX密度在不同的水平上保持平衡。虽然ATM和DNA-PKcs都产生γ-H2AX，但只有ATM将γ-H2AX促进到最大距离并维持γ-H2AX密度。MDC1对dsb附近高密度γ-H2AX的形成至关重要，但对远端序列γ-H2AX的生成却不是必需的。染色质中H2AX水平的降低会影响γ-H2AX的密度，但不会影响其形成的距离。我们的数据表明，H2AX促进了γ-H2AX的自我强化机制，保留了MDC1并激活了dsb附近染色质中的ATM，并促进了H2AX的持续局部磷酸化。
A hallmark of the cellular response to DNA double strand breaks (DSBs) is histone H2AX phosphorylation in chromatin to generate γ-H2AX. Here, we demonstrate that γ-H2AX densities increase transiently along DNA strands as they are broken and repaired in G1 phase cells. The region across which γ-H2AX forms does not spread as DSBs persist, rather γ-H2AX densities equilibrate at distinct levels within a fixed distance from DNA ends. Although both ATM and DNA-PKcs generate γ-H2AX, only ATM promotes γ-H2AX to maximal distance and maintains γ-H2AX densities. MDC1 is essential for γ-H2AX formation at high densities near DSBs, but not for generation of γ-H2AX over distal sequences. Reduced H2AX levels in chromatin impair the density, but not the distance of γ-H2AX formed. Our data indicate that H2AX fuels a γ-H2AX self-reinforcing mechanism that retains MDC1 and activated ATM in chromatin near DSBs and promotes continued local phosphorylation of H2AX.
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影响因子：
16
作者：
Chowdhury, Dipanjan;Xu, Xingzhi;Zhong, Xueyan;Ahmed, Fariyal;Zhong, Jianing;Liao, Ji;Dykxhoorn, Derek M.;Weinstock, David M.;Pfeifer, Gerd P.;Lieberman, Judy
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作者：
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通讯作者：
Nussenzweig, A