Inhibition of Crm1-p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation
Inhibition of Crm1-p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation
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DOI：
10.1038/ncb1638
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发表时间：
2007-10-01
影响因子：
21.3
通讯作者：
Fukasawa, Kenji
中科院分区：
文献类型：
--
作者：
Kanai, Masayuki;Hanashiro, Kazuhiko;Fukasawa, Kenji
聚（ADP-核糖）聚合酶1（PARP- 1）和p53是DNA损伤反应中的两个关键蛋白。尽管已知PARP 1可使p53聚（ADP-核糖基）化，但这种修饰的作用仍不清楚.在这里，我们通过PARP- 1鉴定了p53的主要多聚（ADP-核糖基）化位点，并发现PARP-1介导的多聚（ADP-核糖基）化阻断了p53与核输出受体Crm 1之间的相互作用，导致p53的核积累。这些发现在DNA损伤反应中将PARP- 1和p53分子联系起来，为p53如何在细胞核中积累以响应DNA损伤提供了机制。PARP- 1通过与受损DNA结合而变得超活化，受损DNA进而使p53聚腺苷二磷酸核糖基化。核输出机制不能靶向聚（ADP-核糖基）化的p53，促进p53在核中的积累，其中p53发挥其反式激活功能.
Poly( ADP- ribose) polymerase 1 (PARP- 1) and p53 are two key proteins in the DNA-damage response. Although PARP1 is known to poly( ADP- ribosyl) ate p53, the role of this modification remains elusive. Here, we identify the major poly( ADP- ribosyl) ated sites of p53 by PARP- 1 and find that PARP-1-mediated poly( ADP- ribosyl) ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP- 1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage. PARP- 1 becomes super-activated by binding to damaged DNA, which in turn poly( ADP- ribosyl) ates p53. The nuclear export machinery is unable to target poly( ADP- ribosyl) ated p53, promoting accumulation of p53 in the nucleus where p53 exerts its transactivational function.