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The roles of polymerases ν and θ in the replicative bypass of O 6- and N 2-alkyl-2'-deoxyguanosine lesions in human cells.
Journal of Biological Chemistry ( IF 5.5 ) Pub Date : 2020-04-03 , DOI: 10.1074/jbc.ra120.012830
Hua Du 1 , Pengcheng Wang 1 , Jun Wu 1 , Xiaomei He 1 , Yinsheng Wang 2
Affiliation  

Exogenous and endogenous chemicals can react with DNA to produce DNA lesions that may block DNA replication. Not much is known about the roles of polymerase (Pol) ν and Pol θ in translesion synthesis (TLS) in cells. Here, we examined the functions of both polymerases in bypassing the major-groove O 6-alkyl-2'-deoxyguanosine (O 6-alkyl-dG) and the minor-groove N 2-alkyl-dG lesions in human cells, where the alkyl groups are ethyl (Et), n-butyl (nBu), and, for O 6-alkyl-dG, pyridyloxobutyl (POB). We found that Pol ν and Pol θ promote TLS across the major-groove O 6-alkyl-dG lesions. The O 6-alkyl-dG lesions mainly induced G->A mutations, which were modulated by the two TLS polymerases and the structures of the alkyl groups. Simultaneous ablation of Pol ν and Pol θ resulted in diminished mutation frequencies for all three O 6-alkyl-dG lesions, depletion of Pol ν alone reduced mutations only for O 6-nBu-dG, and sole loss of Pol θ attenuated the mutation rates for both O 6-nBu-dG and O 6-POB-dG. Replication across the two N 2-alkyl-dG lesions was error-free, and Pol ν and Pol θ were dispensable for their replicative bypass. Together, our results provide critical knowledge about the involvement of Pol ν and Pol θ in bypassing alkylated guanine lesions in human cells.

中文翻译:

聚合酶ν和θ在人细胞中O 6和N 2-烷基-2'-脱氧鸟苷损伤的复制旁路中的作用。

外源性和内源性化学物质可与DNA反应产生DNA损伤,从而可能阻止DNA复制。关于聚合酶(Pol)ν和Polθ在细胞内病灶合成(TLS)中的作用,人们所知甚少。在这里,我们研究了两种聚合酶在人类细胞中绕过主要凹槽的O 6-烷基-2'-脱氧鸟苷(O 6-烷基-dG)和次要凹槽的N 2-烷基-dG损伤中的功能。烷基是乙基(Et),正丁基(nBu),对于O 6-烷基-dG,是吡啶基氧丁基(POB)。我们发现,Polν和Polθ可以在主要凹槽的O 6-烷基-dG病变中促进TLS。O 6-烷基-dG损伤主要诱导G-> A突变,这是由两个TLS聚合酶和烷基结构调节的。Polν和Polθ的同时消融导致所有三个O 6-烷基-dG损伤的突变频率降低,单独去除Polν只会减少O 6-nBu-dG的突变,而仅丢失Polθ会减弱O 6-nBu-dG和O 6-POB-dG的突变率。跨越两个N 2-烷基-dG病变的复制没有错误,并且Polν和Polθ对于它们的复制旁路是必不可少的。总之,我们的结果提供了关于Polν和Polθ绕过人类细胞中烷基化鸟嘌呤损伤的关键知识。
更新日期:2020-04-03
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