The roles of DNA polymerase ζ and the Y family DNA polymerases in promoting or preventing genome instability.
The roles of DNA polymerase ζ and the Y family DNA polymerases in promoting or preventing genome instability.
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DOI：
10.1016/j.mrfmmm.2012.11.002
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发表时间：
2013-03
影响因子：
2.3
通讯作者：
Canman, Christine E.
中科院分区：
文献类型：
--
作者：
Sharma, Shilpy;Helchowski, Corey M.;Canman, Christine E.
关键词：
癌细胞显示出许多异常特征，这些异常特征由突变率升高和基因组不稳定性引发和维持。通过DNA损伤反应（DDR）网络持续调查染色体DNA是否存在损伤或被阻断的复制叉。DDR是复杂的并且包括细胞周期检查点的激活、DNA修复、基因转录和细胞凋亡的诱导。复制受损的基因组与分叉崩溃和基因组不稳定的风险增加有关。因此，DNA损伤耐受（DDT）途径也用于增强存活，并且涉及将跨损伤DNA合成（TLS）聚合酶募集到复制叉阻断位点或复制完成后留下的单链DNA缺口，以便在有丝分裂前将DNA恢复到其双链形式。TLS聚合酶专门用于插入与DNA加合物、脱碱基位点或DNA交联相对的核苷酸。根据定义，DDT途径不参与受损DNA的实际修复，但提供了一种在复制期间耐受DNA损伤的机制，从而增加存活率并减少基因组不稳定的机会。然而，这可能与增加的诱变有关。在这篇综述中，我们将描述Y家族聚合酶（Rev1，Polη，Pol I和Polκ）和DNA聚合酶β在病变旁路，诱变和防止基因组不稳定性中的专门功能，后者是由于在DNA修复中的新认识的作用。最近描述的范科尼贫血途径在调节Rev 1和Polζ依赖性TLS中的作用也从它们参与TLS、链间交联修复和同源重组的角度进行了讨论。
Cancer cells display numerous abnormal characteristics which are initiated and maintained by elevated mutation rates and genome instability. Chromosomal DNA is continuously surveyed for the presence of damage or blocked replication forks by the DNA Damage Response (DDR) network. The DDR is complex and includes activation of cell cycle checkpoints, DNA repair, gene transcription, and induction of apoptosis. Duplicating a damaged genome is associated with elevated risks to fork collapse and genome instability. Therefore, the DNA Damage Tolerance (DDT) pathway is also employed to enhance survival and involves the recruitment of translesion DNA synthesis (TLS) polymerases to sites of replication fork blockade or single stranded DNA gaps left after the completion of replication in order to restore DNA to its double stranded form before mitosis. TLS polymerases are specialized for inserting nucleotides opposite DNA adducts, abasic sites, or DNA crosslinks. By definition, the DDT pathway is not involved in the actual repair of damaged DNA, but provides a mechanism to tolerate DNA lesions during replication thereby increasing survival and lessening the chance for genome instability. However this may be associated with increased mutagenesis. In this review, we will describe the specialized functions of Y family polymerases (Rev1, Polη, Polι and Polκ) and DNA polymerase ζ in lesion bypass, mutagenesis, and prevention of genome instability, the latter due to newly appreciated roles in DNA repair. The recently described role of the Fanconi anemia pathway in regulating Rev1 and Polζ-dependent TLS is also discussed in terms of their involvement in TLS, interstrand crosslink repair, and homologous recombination.
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