Activation of the ATR kinase by the RPA-binding protein ETAA1
Activation of the ATR kinase by the RPA-binding protein ETAA1
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DOI：
10.1038/ncb3422
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发表时间：
2016-11-01
影响因子：
21.3
通讯作者：
Mailand, Niels
中科院分区：
文献类型：
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作者：
Haahr, Peter;Hoffmann, Saskia;Mailand, Niels
干扰DNA复制后ATR激酶的激活依赖于一个复杂的机制，包括ATR通过其结合伙伴ATRIP招募到rpa包裹的单链DNA，以及TopBP1刺激ATR激酶活性。在这里，我们在脊椎动物中发现了一个独立的ATR激活途径，由未表征的蛋白ETAA1（尤文氏肿瘤相关抗原1）介导。人类ETAA1通过双rpa结合基序在DNA损伤位点积累，并在基因毒性损伤后促进复制叉的进展和完整性、ATR信号传导和细胞存活。从机制上讲，这需要在ETAA1中存在一个保守结构域，该结构域可以独立于TopBP1直接有效地刺激ATR激酶活性。ETAA1和TopBP1的同时缺失会导致以大量基因组不稳定和atr依赖信号的消失为特征的合成致死率。我们的研究结果表明，平行的topbp1和etaa1介导的途径是ATR激活的基础，它们的联合作用对于应对复制应激是必不可少的。
Activation of the ATR kinase following perturbations to DNA replication relies on a complex mechanism involving ATR recruitment to RPA-coated single-stranded DNA via its binding partner ATRIP and stimulation of ATR kinase activity by TopBP1. Here, we discovered an independent ATR activation pathway in vertebrates, mediated by the uncharacterized protein ETAA1 (Ewing's tumour-associated antigen 1). Human ETAA1 accumulates at DNA damage sites via dual RPA-binding motifs and promotes replication fork progression and integrity, ATR signalling and cell survival after genotoxic insults. Mechanistically, this requires a conserved domain in ETAA1 that potently and directly stimulates ATR kinase activity independently of TopBP1. Simultaneous loss of ETAA1 and TopBP1 gives rise to synthetic lethality characterized by massive genome instability and abrogation of ATR-dependent signalling. Our findings demonstrate that parallel TopBP1-and ETAA1-mediated pathways underlie ATR activation and that their combined action is essential for coping with replication stress.