The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks.
The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks.
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DOI：
10.1038/nsmb.2335
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发表时间：
2012-06-10
影响因子：
16.8
通讯作者：
Oliver AW
中科院分区：
文献类型：
--
作者：
Ali AAE;Timinszky G;Arribas-Bosacoma R;Kozlowski M;Hassa PO;Hassler M;Ladurner AG;Pearl LH;Oliver AW
聚（adp -核糖）聚合酶I （PARP1）是一种主要的DNA损伤传感器，其（adp -核糖）聚合酶活性通过与DNA断裂的相互作用而受到急性调节。在DNA损伤位点激活后，PARP1通过共价添加adp -核糖的长支链聚合物来修饰自身和其他蛋白质，这反过来又招募下游DNA修复和染色质重塑因子。PARP1通过其n端DNA结合结构域（DBD）识别DNA损伤，DBD由一个不寻常的锌指结构域（ZnF）的串联重复组成。我们现在已经确定了人类PARP1-DBD与DNA断裂结合的晶体结构。随着PARP1在体内DNA损伤位点招募的功能分析，该结构揭示了一个二聚体组装，其中来自单独PARP1分子的ZnF1和ZnF2结构域形成一个链断裂识别模块，通过促进其二聚化和随后的反式自修饰来帮助激活PARP1。
Poly(ADP-ribose) polymerase I (PARP1) is a primary DNA damage sensor whose (ADP-ribose) polymerase activity is acutely regulated by interaction with DNA breaks. Upon activation at sites of DNA damage, PARP1 modifies itself and other proteins by covalent addition of long branched polymers of ADP-ribose, which in turn recruit downstream DNA repair and chromatin remodelling factors. PARP1 recognizes DNA damage through its N-terminal DNA-binding domain (DBD), which consists of a tandem repeat of an unusual zinc-finger (ZnF) domain. We have now determined the crystal structure of the human PARP1-DBD bound to a DNA break. Along with functional analysis of PARP1 recruitment to sites of DNA damage in vivo, the structure reveals a dimeric assembly whereby ZnF1 and ZnF2 domains from separate PARP1 molecules form a strand-break recognition module that helps activate PARP1 by facilitating its dimerization and consequent trans-automodification.