小柯机器人

HELQ是一种由RPA和RAD51调节的双功能DSB修复酶
2021-12-26 14:37

英国弗朗西斯·克里克研究所Simon J. Boulton等研究人员合作发现,HELQ是一种由RPA和RAD51调节的双功能DNA双链断裂(DSB)修复酶。2021年12月22日,《自然》杂志在线发表了这项成果。

据研究人员介绍,DSB是有害的病变,其不正确的修复可以推动癌症的发展。HELQ是一个具有3′到5′极性的超家族2号螺旋酶,它在小鼠中的中断会导致生殖细胞丧失、不育,并增加对卵巢和垂体肿瘤的易感性。在细胞水平上,HELQ的缺陷导致对顺铂和丝裂霉素C的不敏感,以及在DNA损伤后RAD51病灶的持续存在。值得注意的是,HELQ与RPA和RAD51类似物BCDX2复合物结合,但这些相互作用的相关性以及HELQ如何在DSB修复中发挥作用仍不清楚。
 
研究人员表明,HELQ的螺旋酶活性和一个以前未被重视的DNA链退火功能受到RPA和RAD51的不同调节。通过生物化学分析和单分子成像,研究人员发现RAD51与HELQ形成一个复合体,并强烈刺激HELQ在DNA解旋过程中的易位。相比之下,RPA抑制了HELQ的DNA解旋,但强烈刺激了DNA链的退火。从机理上讲,HELQ具有捕获RPA结合DNA链的内在能力,然后置换RPA来促进互补序列的退火。最后,研究人员表明,细胞中HELQ的缺乏损害了单链退火和微同源介导的末端连接途径,并导致同源重组过程中对长链基因转换链的偏好。因此,这些研究结果表明,HELQ通过共同因子依赖性地调控内在的易位酶和DNA链退火活性,从而参与了DSB修复的多个环节。
 
附:英文原文
 
Title: HELQ is a dual-function DSB repair enzyme modulated by RPA and RAD51

Author: Anand, Roopesh, Buechelmaier, Erika, Belan, Ondrej, Newton, Matthew, Vancevska, Aleksandra, Kaczmarczyk, Artur, Takaki, Tohru, Rueda, David S., Powell, Simon N., Boulton, Simon J.

Issue&Volume: 2021-12-22

Abstract: DNA double-stranded breaks (DSBs) are deleterious lesions, and their incorrect repair can drive cancer development1. HELQ is a superfamily 2 helicase with 3′ to 5′ polarity, and its disruption in mice confers germ cells loss, infertility and increased predisposition to ovarian and pituitary tumours2,3,4. At the cellular level, defects in HELQ result in hypersensitivity to cisplatin and mitomycin C, and persistence of RAD51 foci after DNA damage3,5. Notably, HELQ binds to RPA and the RAD51-paralogue BCDX2 complex, but the relevance of these interactions and how HELQ functions in DSB repair remains unclear3,5,6. Here we show that HELQ helicase activity and a previously unappreciated DNA strand annealing function are differentially regulated by RPA and RAD51. Using biochemistry analyses and single-molecule imaging, we establish that RAD51 forms a complex with and strongly stimulates HELQ as it translocates during DNA unwinding. By contrast, RPA inhibits DNA unwinding by HELQ but strongly stimulates DNA strand annealing. Mechanistically, we show that HELQ possesses an intrinsic ability to capture RPA-bound DNA strands and then displace RPA to facilitate annealing of complementary sequences. Finally, we show that HELQ deficiency in cells compromises single-strand annealing and microhomology-mediated end-joining pathways and leads to bias towards long-tract gene conversion tracts during homologous recombination. Thus, our results implicate HELQ in multiple arms of DSB repair through co-factor-dependent modulation of intrinsic translocase and DNA strand annealing activities.

DOI: 10.1038/s41586-021-04261-0

Source: https://www.nature.com/articles/s41586-021-04261-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0