Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage.
Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage.
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DOI：
10.1093/nar/gkm493
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发表时间：
2007
影响因子：
14.9
通讯作者：
Rouse J
中科院分区：
文献类型：
--
作者：
Munoz IM;Jowsey PA;Toth R;Rouse J
人类(h)PTIP在细胞对DNA损伤的反应中起着重要的但鲜为人知的作用。hPTIP与53BP1肿瘤抑制因子相互作用，但仅当53BP1在DNA损伤后被ATM磷酸化时，尽管这两种蛋白相互作用的机制和意义尚不清楚。在这里，我们确定了53BP1 - ser25中一个单独的atm磷酸化残基，这是53BP1与hPTIP结合所必需的。在体外和体内，phospho-Ser25与hPTIP的结合需要在hPTIP的c端有两对紧密对应的BRCT结构域，而且这两对结构域都不能单独与phospho-Ser25结合，尽管这些BRCT对中的一对可以单独与其他atm磷酸化的表位结合。53BP1和hPTIP的突变阻止了这两种蛋白的相互作用，使细胞对DNA损伤过敏，削弱了ATM信号。hPTIP的c端BRCT结构域对于hPTIP在DNA损伤位点的稳定保留也是必需的，但这似乎与与53BP1的结合无关。因此，hPTIP的BRCT结构域在细胞对DNA损伤的反应中发挥重要作用。
Human (h)PTIP plays important but poorly understood roles in cellular responses to DNA damage. hPTIP interacts with 53BP1 tumour suppressor but only when 53BP1 is phosphorylated by ATM after DNA damage although the mechanism(s) and significance of the interaction of these two proteins are unclear. Here, we pinpoint a single ATM-phosphorylated residue in 53BP1—Ser25—that is required for binding of 53BP1 to hPTIP. Binding of phospho-Ser25 to hPTIP in vitro and in vivo requires two closely apposed pairs of BRCT domains at the C-terminus of hPTIP and neither pair alone can bind to phospho-Ser25, even though one of these BRCT pairs in isolation can bind to other ATM-phosphorylated epitopes. Mutations in 53BP1 and in hPTIP that prevent the interaction of the two proteins, render cells hypersensitive to DNA damage and weaken ATM signalling. The C-terminal BRCT domains of hPTIP are also required for stable retention of hPTIP at sites of DNA damage but this appears to be independent of binding to 53BP1. Thus, the BRCT domains of hPTIP play important roles in the cellular response to DNA damage.
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影响因子：
5.3
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