ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1.
ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1.
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ATR在线粒体上扮演直接的抗凋亡作用，该抗凋亡作用受Prolyl异构酶PIN1的调节。
DOI：
10.1016/j.molcel.2015.08.008
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发表时间：
2015-10-01
期刊：
影响因子：
16
通讯作者：
Zou Y
中科院分区：
文献类型：
--
作者：
Hilton BA;Li Z;Musich PR;Wang H;Cartwright BM;Serrano M;Zhou XZ;Lu KP;Zou Y
ATR是一种类PI3K蛋白激酶，在调节DNA损伤应答中起关键作用。其核检查点激酶功能已有充分记载，但对其在细胞核外的功能知之甚少。在此我们报道，ATR在响应紫外线损伤时在线粒体具有抗凋亡活性，且此活性与其标志性的检查点/激酶活性以及搭档ATRIP无关。ATR包含一个类似BH3的结构域，该结构域使ATR与tBid在线粒体相互作用，抑制细胞色素c的释放和细胞凋亡。ATR的这种线粒体活性被Pin1下调，Pin1在磷酸化的丝氨酸428 - 脯氨酸429基序处将ATR从顺式异构体异构化为反式异构体。然而，紫外线通过DAPK1使Pin1失活，稳定了具有促存活作用的顺式异构体ATR。相反，细胞核中的ATR无论是否有紫外线照射都保持反式异构体形式。ATR的这种细胞质应答可能为所观察到的ATR在抑制癌症发生中的抗凋亡作用以及其在使抗癌药物对癌细胞杀伤更敏感方面的抑制作用提供了一种机制。
ATR, a PI3K-like protein kinase, plays a key role in regulating DNA damage responses. Its nuclear checkpoint kinase function is well documented but little is known about its function outside the nucleus. Here we report that ATR has an antiapoptotic activity at mitochondria in response to UV damage, and this activity is independent of its hallmark checkpoint/kinase activity and partner ATRIP. ATR contains a BH3-like domain that allows ATR-tBid interaction at mitochondria, suppressing cytochrome c release and apoptosis. This mitochondrial activity of ATR is downregulated by Pin1 that isomerizes ATR from cis-isomer to trans-isomer at the phosphorylated-Ser428-Pro429 motif. However, UV inactivates Pin1 via DAPK1, stabilizing the pro-survival cis-isomeric ATR. In contrast, nuclear ATR remains in the trans-isoform disregarding UV. This cytoplasmic response of ATR may provide a mechanism for the observed antiapoptotic role of ATR in suppressing carcinogenesis and its inhibition in sensitizing anticancer agents for killing of cancer cells.