Ikura Masae, Furuya Kanji, Fukuto Atsuhiko, Matsuda Ryo, Adachi Jun, Matsuda Tomonari, Kakizuka Akira, Ikura Tsuyoshi
Laboratory of Chromatin Regulatory Network, Department of Mutagenesis, Radiation Biology Center, Kyoto University, Kyoto, Japan.
Department of Radiation Systems, Radiation Biology Center, Kyoto University, Kyoto, Japan.
Mol Cell Biol. 2016 May 2;36(10):1595-607. doi: 10.1128/MCB.01085-15. Print 2016 May 15.
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.
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，如DNA修复和转录。响应DNA损伤时，由TIP60催化的组蛋白变体H2AX中赖氨酸5的乙酰化在促进组蛋白交换中起关键作用；然而，详细的分子机制仍不清楚。在这里，我们表明TIP60复合物包含聚（ADP-核糖）聚合酶1（PARP-1）。PARP-1是DNA损伤位点处染色质上H2AX快速交换所必需的。已知PARP-1动态结合受损染色质，对随后其他修复因子的募集至关重要，其自身聚（ADP-核糖）基化对这种动态变化是必需的。我们还表明，TIP60介导的组蛋白H2AX赖氨酸5的乙酰化而非H2AX的磷酸化，是PARP-1的ADP-核糖基化活性及其与受损染色质动态结合所必需的。我们的结果表明H2AX的K5乙酰化与PARP-1之间存在相互调节，这可能调节染色质结构以促进损伤位点处的DNA代谢。这可以解释PARP-1在各种DNA损伤反应中相当不明确的作用。
