Ewing Tumor-associated Antigen 1 Interacts with Replication Protein A to Promote Restart of Stalled Replication Forks
Ewing Tumor-associated Antigen 1 Interacts with Replication Protein A to Promote Restart of Stalled Replication Forks
复制标题
尤因肿瘤相关抗原 1 与复制蛋白 A 相互作用，促进停滞的复制叉重新启动
DOI：
10.1074/jbc.c116.747758
复制
发表时间：
2016-10-14
影响因子：
4.8
通讯作者：
Xu, Dongyi
中科院分区：
文献类型：
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作者：
Feng, Sumin;Zhao, Yichao;Xu, Dongyi
复制蛋白A（RPA）复合物结合在停滞的复制叉处产生的单链DNA，并招募其他DNA修复蛋白来促进这些叉的恢复。在这里，我们确定了尤文肿瘤相关抗原1（ETAA1），它与胰腺癌的易感性有关，作为一种新的修复蛋白，被RPA招募到停滞的叉子上。我们证明ETAA1通过两个区域与RPA相互作用，每个区域类似于两个先前确定的RPA结合结构域，分别为RPA 70 N结合基序和RPA 32 C结合基序。为了应对复制压力，ETAA1被招募到停滞的分叉，在那里它与RPA共定位，当RPA耗尽时，这种招募就会减少。值得注意的是，ETAA1基因的失活增加了停滞复制叉的崩溃水平，并降低了这些叉的恢复效率。此外，上位性分析显示ETAA1以共济失调毛细血管扩张和Rad3相关蛋白（ATR）独立的方式稳定停滞的复制叉。因此，我们的研究结果表明，ETAA1是一种新的RPA相互作用蛋白，促进停滞的复制叉的重新启动。
The replication protein A (RPA) complex binds single-stranded DNA generated at stalled replication forks and recruits other DNA repair proteins to promote recovery of these forks. Here, we identify Ewing tumor-associated antigen 1 (ETAA1), which has been linked to susceptibility to pancreatic cancer, as a new repair protein that is recruited to stalled forks by RPA. We demonstrate that ETAA1 interacts with RPA through two regions, each of which resembles two previously identified RPA-binding domains, RPA70N-binding motif and RPA32C-binding motif, respectively. In response to replication stress, ETAA1 is recruited to stalled forks where it colocalizes with RPA, and this recruitment is diminished when RPA is depleted. Notably, inactivation of the ETAA1 gene increases the collapse level of the stalled replication forks and decreases the recovery efficiency of these forks. Moreover, epistasis analysis shows that ETAA1 stabilizes stalled replication forks in an ataxia telangiectasia and Rad3-related protein (ATR)-independent manner. Thus, our results reveal that ETAA1 is a novel RPA-interacting protein that promotes restart of stalled replication forks.