Poly(ADP-ribose) polymerase 1 is inhibited by a histone H2A variant, MacroH2A, and contributes to silencing of the inactive X chromosome
Poly(ADP-ribose) polymerase 1 is inhibited by a histone H2A variant, MacroH2A, and contributes to silencing of the inactive X chromosome
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DOI：
10.1074/jbc.m610502200
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发表时间：
2007-04-27
影响因子：
4.8
通讯作者：
Panning, Barbara
中科院分区：
文献类型：
--
作者：
Nusinow, Dmitri A.;Hernandez-Munoz, Inmaculada;Panning, Barbara
多聚(ADP-核糖)聚合酶1(PARP-1)是一种核酶，参与染色质结构的调节、基因表达的调控和DNA损伤的感知。在这里，我们报告了PARP-1酶活性被宏H_2A抑制，这是一种富含兼性异染色质的脊椎动物组蛋白H_2A变体。MacroH_2A家族成员有一个大的C-末端非组蛋白结构域和H_2A样组蛋白结构域。MacroH2A1.2和PARP-1通过NHD在体内和体外相互作用。在体外，每个大分子H_2A家族成员的NHD足以抑制PARP-1酶的活性。宏H_2A1.2的NHD是PARP-1催化活性的混合抑制剂，对PARP-1的催化活性和底物结合亲和力都有影响。RNA干扰使PARP-1缺失，导致失活X染色体上的一个报告基因重新激活，表明PARP-1参与了沉默的维持。这些结果表明，大分子H_2A在基因沉默中的作用之一是抑制PARP-1的酶活性，这可能影响PARP-1与染色质的结合。
Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in modulating chromatin structure, regulation of gene expression, and sensing DNA damage. Here, we report that PARP-1 enzymatic activity is inhibited by macroH2A, a vertebrate histone H2A variant that is enriched on facultative heterochromatin. MacroH2A family members have a large C-terminal non-histone domain (NHD) and H2A-like histone domain. MacroH2A1.2 and PARP-1 interact in vivo and in vitro via the NHD. The NHD of each macroH2A family member was sufficient to inhibit PARP-1 enzymatic activity in vitro. The NHD of macroH2A1.2 was a mixed inhibitor of PARP-1 catalytic activity, with affects on both catalytic activity and the substrate binding affinity of PARP-1. Depletion of PARP-1 by RNA interference caused reactivation of a reporter gene on the inactive X chromosome, demonstrating that PARP-1 participates in the maintenance of silencing. These results suggest that one function of macroH2A in gene silencing is to inhibit PARP-1 enzymatic activity, and this may affect PARP-1 association with chromatin.