RECQ1 plays a distinct role in cellular response to oxidative DNA damage
RECQ1 plays a distinct role in cellular response to oxidative DNA damage
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DOI：
10.1016/j.dnarep.2012.04.003
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发表时间：
2012-06-01
期刊：
影响因子：
3.8
通讯作者：
LaRocque, Jeannine R.
中科院分区：
文献类型：
--
作者：
Sharma, Sudha;Phatak, Pornima;LaRocque, Jeannine R.
RECQ 1是人类中最丰富的RecQ同源物，但其功能仍然是难以捉摸的。从生物化学上来说。RECQ 1显示出与WRN和BLM不同的底物特异性，表明这些RecQ解旋酶可能执行非重叠功能。我们早期的工作表明RECQ 1缺陷细胞显示自发的基因组不稳定性。我们已经获得了关键证据，表明RECQ 1在氧化DNA损伤修复中具有独特的作用。我们发现，类似于WRN，RECQ 1协会与PARP-1在核提取物，并在体外表现出直接的蛋白质相互作用。已证明WRN或BLM解旋酶的缺乏会导致基础条件下同源重组减少和PARP过度激活。然而. RECQ 1缺陷不会导致未受损细胞中的PARP激活，也不会导致同源重组修复减少。与WRN缺陷形成鲜明对比的是，RECQ 1缺陷细胞在对H2 O2处理的特异性反应中过度激活PARP。RECQ 1缺陷细胞对氧化性DNA损伤更敏感，暴露于氧化应激导致RECQ 1快速可逆地募集到染色质。RECQ 1的染色质定位先于WRN解旋酶，WRN解旋酶已被证明在氧化DNA损伤修复中起作用。然而，这些RecQ解旋酶的氧化DNA损伤诱导的染色质募集与PARP活性无关。由于已知其他RecQ解旋酶与PARP-1相互作用，因此本研究提供了一个范例来描述RecQ同源物在氧化DNA损伤修复中的专门和冗余功能。(C)2012爱思唯尔有限公司版权所有。
RECQ1 is the most abundant RecQ homolog in humans but its functions have remained mostly elusive. Biochemically. RECQ1 displays distinct substrate specificities from WRN and BLM, indicating that these RecQ helicases likely perform non-overlapping functions. Our earlier work demonstrated that RECQ1-deficient cells display spontaneous genomic instability. We have obtained key evidence suggesting a unique role of RECQ1 in repair of oxidative DNA damage. We show that similar to WRN, RECQ1 associates with PARP-1 in nuclear extracts and exhibits direct protein interaction in vitro. Deficiency in WRN or BLM helicases have been shown to result in reduced homologous recombination and hyperactivation of PARP under basal condition. However. RECQ1-deficiency did not lead to PARP activation in undamaged cells and nor did it result in reduction in homologous recombination repair. In stark contrast to what is seen in WRN-deficiency, RECQ1-deficient cells hyperactivate PARP in a specific response to H2O2 treatment. RECQ1-deficient cells are more sensitive to oxidative DNA damage and exposure to oxidative stress results in a rapid and reversible recruitment of RECQ1 to chromatin. Chromatin localization of RECQ1 precedes WRN helicase, which has been shown to function in oxidative DNA damage repair. However, oxidative DNA damage-induced chromatin recruitment of these RecQ helicases is independent of PARP activity. As other RecQ helicases are known to interact with PARP-1, this study provides a paradigm to delineate specialized and redundant functions of RecQ homologs in repair of oxidative DNA damage. (C) 2012 Elsevier B.V. All rights reserved.