A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation
A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation
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DOI：
10.1038/nsmb.1664
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发表时间：
2009-09-01
影响因子：
16.8
通讯作者：
Ladurner, Andreas G.
中科院分区：
文献类型：
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作者：
Timinszky, Gyula;Till, Susanne;Ladurner, Andreas G.
Poly-ADP-核糖化是由PARP酶催化的一种翻译后修饰，在转录和染色质生物学中起作用。在这里，我们证明了不同的宏结构域，包括组蛋白宏H_2A1.1的结构域，被招募到激光产生的DNA损伤诱导的PARP1激活的位置。化学PARP1抑制剂，PARP1敲除和突变的ADP核糖结合残基在大H_2A1.1消除大域招募。值得注意的是，组蛋白宏H_2A1.1感知PARP1激活，瞬时压缩染色质，减少DNA损伤因子Ku70-Ku80的招募并改变伽马-H_2AX模式，而剪接变异体宏H_2A1.2缺乏聚ADP-核糖结合，不介导PARP1激活时的染色质重排。与ADP-核糖形成的络合物中的大分子H_2A1.1大分子域的结构建立了聚ADP-核糖的帽子结合功能，并揭示了配体结合时大分子结构域的构象变化。因此，我们将大结构域识别为直接感觉体内PARP激活的模块，并将大H_2A组蛋白建立为染色质可塑性的动态调节因子。
Poly-ADP-ribosylation is a post-translational modification catalyzed by PARP enzymes with roles in transcription and chromatin biology. Here we show that distinct macrodomains, including those of histone macroH2A1.1, are recruited to sites of PARP1 activation induced by laser-generated DNA damage. Chemical PARP1 inhibitors, PARP1 knockdown and mutation of ADP-ribose-binding residues in macroH2A1.1 abrogate macrodomain recruitment. Notably, histone macroH2A1.1 senses PARP1 activation, transiently compacts chromatin, reduces the recruitment of DNA damage factor Ku70-Ku80 and alters gamma-H2AX patterns, whereas the splice variant macroH2A1.2, which is deficient in poly-ADP-ribose binding, does not mediate chromatin rearrangements upon PARP1 activation. The structure of the macroH2A1.1 macrodomain in complex with ADP-ribose establishes a poly-ADP-ribose capbinding function and reveals conformational changes in the macrodomain upon ligand binding. We thus identify macrodomains as modules that directly sense PARP activation in vivo and establish macroH2A histones as dynamic regulators of chromatin plasticity.