Human Rvbl/Tip49 is required for the histone acetyltransferase activity of Tip60/NuA4 and for the Downregulation of phosphorylation on H2AX after DNA damage
Human Rvbl/Tip49 is required for the histone acetyltransferase activity of Tip60/NuA4 and for the Downregulation of phosphorylation on H2AX after DNA damage
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DOI：
10.1128/mcb.01983-07
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发表时间：
2008-04-01
影响因子：
5.3
通讯作者：
Dutta, Anindya
中科院分区：
文献类型：
--
作者：
Jha, Sudhakar;Shibata, Etsuko;Dutta, Anindya
染色质重塑因子在转录中的作用已经得到了很好的证实，但是染色质重塑复合物和DNA修复之间的联系仍然没有被探索。人Rvb1和Rvb2是高度保守的AAA（+）ATP结合蛋白，是多种染色质重塑复合物的一部分，如Ino80、SNF2related CBP activator protein（SRCAP）和Tip60/NuA4复合物，但其分子功能尚不清楚。在细胞暴露于LJV照射或丝裂霉素C、顺铂、喜树碱或依托泊苷后，Rvb1的耗竭增加了染色质相关H2AX磷酸化的量和持久性，而不增加DNA损伤的量。Tip60耗竭，而不是Ino80或SRCAP耗竭，模拟Rvb1耗竭对H2AX磷酸化的影响。Rvb1是Tip60复合物的组蛋白乙酰转移酶（HAT）活性所必需的，并且在磷酸-H2AX的去磷酸化之前需要组蛋白H4乙酰化。因此，由于Rvb1在维持Tip60/NuA4的HAT活性中的作用，Rvb1对于磷酸化-H2AX的去磷酸化是关键的，这暗示了Rvb1-Tip60复合物在DNA损伤后细胞的染色质重塑反应中的作用。
The role of chromatin-remodeling factors in transcription is well established, but the link between chromatin-remodeling complexes and DNA repair remains unexplored. Human Rvb1 and Rvb2 are highly conserved AAA(+) ATP binding proteins that are part of various chromatin-remodeling complexes, such as Ino80, SNF2related CBP activator protein (SRCAP), and Tip60/NuA4 complexes, but their molecular function is unclear. The depletion of Rvb1 increases the amount and persistence of phosphorylation on chromatin-associated H2AX after the exposure of cells to LJV irradiation or to mitomycin C, cisplatin, camptothecin, or etoposide, without increasing the amount of DNA damage. Tip60 depletion, but not Ino80 or SRCAP depletion, mimics the effect of Rvb1 depletion on H2AX phosphorylation. Rvb1 is required for the histone acetyltransferase (HAT) activity of the Tip60 complex, and histone H4 acetylation is required prior to the dephosphorylation of phospho-H2AX. Thus, Rvb1 is critical for the dephosphorylation of phospho-H2AX due to the role of Rvb1 in maintaining the HAT activity of Tip60/NuA4, implicating the Rvb1-Tip60 complex in the chromatin-remodeling response of cells after DNA damage.