Error-prone lesion bypass by human DNA polymerase eta.
Error-prone lesion bypass by human DNA polymerase eta.
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DOI：
10.1093/nar/28.23.4717
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发表时间：
2000-12
影响因子：
14.9
通讯作者：
Yanbin Zhang;F. Yuan;Xiaohua Wu;O. Rechkoblit;John-Stephen A Taylor;N. Geacintov;Zhigang Wang
中科院分区：
文献类型：
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作者：
Yanbin Zhang;F. Yuan;Xiaohua Wu;O. Rechkoblit;John-Stephen A Taylor;N. Geacintov;Zhigang Wang
DNA损伤旁路是复制过程中对基因组损伤的重要细胞反应。人DNA聚合酶eta（Pol（eta））由着色性干皮病变异体（XPV）基因编码，已知其具有与TT顺式-顺式环丁烷二聚体相对的无错跨损伤合成活性。使用纯化的人Pol（eta），我们研究了这种聚合酶对其他几种DNA损伤的旁路活性。人Pol（eta）有效地绕过了模板8-氧代鸟嘌呤，以类似的效率在病变对面掺入A或C。人Pol（eta）有效地绕过了模板脱碱基位点，在病变对面掺入A和较不频繁的G。当无碱基位点的5'端的模板碱基是T时，也观察到显著的-1缺失。人Pol（eta）部分绕过模板（+）-反式-抗-苯并[a]芘-N：（2）-dG，并主要掺入A，较少掺入T，最少掺入病变对面的G或C。这种核苷酸掺入的特异性与哺乳动物细胞中（+）-反式-抗-苯并[a]芘-N：（2）-dG损伤的已知突变谱很好地相关。这些结果表明，人Pol（eta）能够在体外进行易错的跨病变DNA合成，并表明Pol（eta）可能绕过某些病变，在人体内产生致突变后果。
DNA lesion bypass is an important cellular response to genomic damage during replication. Human DNA polymerase eta (Pol(eta)), encoded by the Xeroderma pigmentosum variant (XPV) gene, is known for its activity of error-free translesion synthesis opposite a TT cis-syn cyclobutane dimer. Using purified human Pol(eta), we have examined bypass activities of this polymerase opposite several other DNA lesions. Human Pol(eta) efficiently bypassed a template 8-oxoguanine, incorporating an A or a C opposite the lesion with similar efficiencies. Human Pol(eta) effectively bypassed a template abasic site, incorporating an A and less frequently a G opposite the lesion. Significant -1 deletion was also observed when the template base 5' to the abasic site is a T. Human Pol(eta) partially bypassed a template (+)-trans-anti-benzo[a]pyrene-N:(2)-dG and predominantly incorporated an A, less frequently a T, and least frequently a G or a C opposite the lesion. This specificity of nucleotide incorporation correlates well with the known mutation spectrum of (+)-trans-anti-benzo[a]pyrene-N:(2)-dG lesion in mammalian cells. These results show that human Pol(eta) is capable of error-prone translesion DNA syntheses in vitro and suggest that Pol(eta) may bypass certain lesions with a mutagenic consequence in humans.