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首页> 外文期刊>Molecular and Cellular Biology >Coordinated Regulation of TIP60 and Poly(ADP-Ribose) Polymerase 1 in Damaged-Chromatin Dynamics
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Coordinated Regulation of TIP60 and Poly(ADP-Ribose) Polymerase 1 in Damaged-Chromatin Dynamics

机译：TIP60和聚（ADP-核糖）聚合酶1在染色质动力学中的协同调节。

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摘要

The dynamic exchange of histones alleviates the nucleosome barrier and simultaneously facilitates various aspects of cellular DNA metabolism, such as DNA repair and transcription. In response to DNA damage, the acetylation of Lys5 in the histone variant H2AX, catalyzed by TIP60, plays a key role in promoting histone exchange; however, the detailed molecular mechanism still is unclear. Here, we show that the TIP60 complex includes poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 is required for the rapid exchange of H2AX on chromatin at DNA damage sites. It is known that PARP-1 binds dynamically to damaged chromatin and is crucial for the subsequent recruitment of other repair factors, and its auto-poly(ADP-ribosyl)ation is required for the dynamics. We also show that the acetylation of histone H2AX at Lys5 by TIP60, but not the phosphorylation of H2AX, is required for the ADP-ribosylation activity of PARP-1 and its dynamic binding to damaged chromatin. Our results indicate the reciprocal regulation of K5 acetylation of H2AX and PARP-1, which could modulate the chromatin structure to facilitate DNA metabolism at damage sites. This could explain the rather undefined roles of PARP-1 in various DNA damage responses.
机译：组蛋白的动态交换减轻了核小体屏障，同时促进了细胞DNA代谢的各个方面，例如DNA修复和转录。响应DNA损伤，由TIP60催化的组蛋白变体H2AX中Lys5的乙酰化在促进组蛋白交换中起关键作用。然而，具体的分子机制仍不清楚。在这里，我们显示TIP60复杂包括聚（ADP-核糖）聚合酶1（PARP-1）。在DNA损伤部位的染色质上快速交换H2AX需要PARP-1。众所周知，PARP-1动态结合到受损的染色质上，对于随后的其他修复因子的募集至关重要，动力学需要其自动聚（ADP-核糖基）化。我们还显示，TIP60在Lys5处将组蛋白H2AX乙酰化，而不是H2AX磷酸化，对于PARP-1的ADP-核糖基化活性及其与受损染色质的动态结合是必需的。我们的结果表明，H2AX和PARP-1的K5乙酰化的相互调节，可以调节染色质结构，促进损伤部位的DNA代谢。这可以解释PARP-1在各种DNA损伤反应中的作用尚未明确。

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