DNA聚合酶θ:易错的多功能DNA末端修复分子  

DNA Polymeraseθ:a Multifunctional and Error-prone DNA End Repair Enzyme

作　　者：王瑶 陈国江 冯健男 石艳春[1] 王晶 郑源强[1] WANG Yao;CHEN Guo-Jiang;FENG Jian-Nan;SHI Yan-Chun;WANG Jing;ZHENG Yuan-Qiang(Key Laboratory of Molecular Biology of Inner Mongolia Autonomous Region,Inner Mongolia Medical University,Hohhot 010058,China;State Key Laboratory of Toxicology and Medical Countermeasures,Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences,Academy of Military Sciences,Beijing 100850,China)

机构地区：[1]内蒙古医科大学,内蒙古自治区分子生物学重点实验室,呼和浩特010058 [2]军事科学院军事医学研究院毒物药物研究所,抗毒药物与毒理学国家重点实验室,北京100850

出　　处：《生物化学与生物物理进展》2024年第3期493-503,共11页Progress In Biochemistry and Biophysics

基　　金：北京市自然科学基金(7222262);国家自然科学基金(31900676)资助项目。

摘　　要：DNA聚合酶θ(DNA polymerase theta,Polθ)是一种广泛存在于动植物中的DNA修复酶。它在选择性末端连接(alternative end-joining,Alt-EJ)途径中发挥着关键作用,常参与DNA双链断裂(DNA double-strand breaks,DSB)损伤修复。在正常生理状态下,Polθ主要调控基因组稳定性。然而,在恶性肿瘤发生时,Polθ表现出异常高表达水平,并参与调控肿瘤细胞的恶性转变过程。研究表明,抑制Polθ活性可导致同源重组(homologous recombination,HR)缺陷的肿瘤细胞发生合成致死(synthetic lethality,SL)。因此,已经开发出多种针对Polθ的小分子抑制剂,可与其他化疗药物联合使用以抑制恶性肿瘤的发展。此外,敲除或抑制Polθ活性还能增加HR修复效率,从而提高外源基因靶向整合效果。本文综述了Polθ及其介导的Alt-EJ修复机制在生物学功能方面的最新研究进展,为靶向Polθ在肿瘤治疗和基因编辑方面的应用提供理论基础。DNA polymerase theta(Polθ),also known as DNA polymeraseθ,is the member of the DNA polymerase A family and plays a crucial role in the repair of DNA double-strand breaks(DSB).Polθhas 3 distinct structural domains:the N-terminal helicase-like domain with a conserved sequence,the C-terminal polymerase domain,and the central domain,which is a disordered sequence connecting these two regions.Notably,Polθis the only known polymerase in eukaryotes that possesses helicase activity.However,it is also an error-prone polymerase.When DNA DSBs occur,a specialized network consisting of at least 4 pathways,including classicalnon homologous end joining(C-NHEJ),homologous recombination(HR),single-strand annealing(SSA),and alternative-end joining(Alt-EJ),is responsible for repairing DNA damage caused by DSBs.In the absence of major DNA repair pathways like HR,cells rely on Alt-EJ pathway mediated by Polθto repair damaged DNA and maintain genomic stability.Nevertheless,due to the low fidelity of Polθ,Alt-EJ repair often leads to errors.Depletion of Polθhas shown to increases DSB formation and compromise genomic stability.Conversely,overexpression of Polθhas been associated with increases DNA damage markers and impairs cell cycle progression.As a result,the impact of Polθon genome stability remains controversial.Furthermore,overexpression of Polθis frequently observed in cancer and is associated with a characteristic mutational signature and poor prognosis.Depleting Polθin an HR-deficient background has been shown to impair cell viability,suggesting a synthetic lethal(SL)relationship between Polθand HR factors.In recent years,targeted chemotherapy drugs that inhibit tumor growth have gained significant attention.However,off-target effects and drug resistance pose challenges for clinical application,particularly with poly-ADP-ribose polymerase inhibitor(PARPi).Blocking Polθactivity in HR-deficient tumor cells has been found to reverse PARPi resistance,making Polθa very promising therapeutic target in cancer treatment.Th

关 键 词：DNA聚合酶θ DNA双链断裂修复 基因组稳定性 肿瘤抑制 靶向整合 

分 类 号：R3[医药卫生—基础医学] R392