Probing the structure and function of polymerase θ helicase-like domain.
Probing the structure and function of polymerase θ helicase-like domain.
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DOI：
10.1016/j.dnarep.2022.103358
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发表时间：
2022-08
期刊：
影响因子：
3.8
通讯作者：
Doublie, Sylvie
中科院分区：
文献类型：
--
作者：
Vanson, Scott;Li, Yuzhen;Wood, Richard D.;Doublie, Sylvie
DNA聚合酶θ是最近发现的双链断裂修复途径θ介导的末端连接（TMEJ）的关键致动器。它是唯一已知的具有3-结构域结构的聚合酶，其含有通过长的中心区域拴系到N-末端解旋酶样结构域（HLD）的独立功能的A家族DNA聚合酶。全长聚合酶θ和分离的HLD在DNA存在下水解ATP，但没有观察到DNA双链体解旋过程。基于序列和结构保守性，HLD被分类为解旋酶超家族II的成员，更具体地，Ski2样家族。特定的亚结构域的组成和组织最接近的古细菌DNA修复解旋酶Hel308和Hjm。尽管HLD与真正的解旋酶相似，但其为什么不能使双链体DNA解旋的潜在结构基础仍然难以捉摸。HLD的活性包括ATP水解、蛋白质置换和互补DNA的退火。这些观察结果导致了对HLD在通过TMEJ进行双链断裂修复的背景下的作用的推测，例如去除单链DNA结合蛋白如RPA和RAD 51以及微同源比对。本文综述了聚合酶θ HLD及其同系物的结构分类和组织，并探讨了其生化活性的新数据。我们得出结论，一个简单的，投机性的模型HLD的作用，TMEJ。
DNA Polymerase θ is the key actuator of the recently identified double-strand break repair pathway, theta-mediated end joining (TMEJ). It is the only known polymerase to have a 3-domain architecture containing an independently functional family A DNA polymerase tethered by a long central region to an N-terminal helicase-like domain (HLD). Full-length polymerase θ and the isolated HLD hydrolyze ATP in the presence of DNA, but no processive DNA duplex unwinding has been observed. Based on sequence and structure conservation, the HLD is classified as a member of helicase superfamily II and, more specifically, the Ski2-like family. The specific subdomain composition and organization most closely resemble that of archaeal DNA repair helicases Hel308 and Hjm. The underlying structural basis as to why the HLD is not able to processively unwind duplex DNA, despite its similarity to bona fide helicases, remains elusive. Activities of the HLD include ATP hydrolysis, protein displacement, and annealing of complementary DNA. These observations have led to speculation about the role of the HLD within the context of double-strand break repair via TMEJ, such as removal of single-stranded DNA binding proteins like RPA and RAD51 and microhomology alignment. This review summarizes the structural classification and organization of the polymerase θ HLD and its homologs and explores emerging data on its biochemical activities. We conclude with a simple, speculative model for the HLD’s role in TMEJ.
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