Noncanonical Mismatch Repair as a Source of Genomic Instability in Human Cells
Noncanonical Mismatch Repair as a Source of Genomic Instability in Human Cells
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DOI：
10.1016/j.molcel.2012.07.006
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发表时间：
2012-09-14
期刊：
影响因子：
16
通讯作者：
Jiricny, Josef
中科院分区：
文献类型：
--
作者：
Pena-Diaz, Javier;Bregenhorn, Stephanie;Jiricny, Josef
错配修复（MMR）是一个关键的抗突变过程，增加了DNA复制和重组的保真度。然而，遗传实验表明，MMR是抗体成熟所必需的，在此过程中，抗原刺激的B细胞的免疫球蛋白位点经历广泛的诱变和重排。在试图阐明后者事件的机制，我们着手寻找条件，妥协MMR保真度。在这里，我们描述了非典型MMR（ncMMR），在这个过程中，MMR途径被激活的各种DNA损伤，而不是错配。ncMMR在很大程度上不依赖于DNA复制，缺乏链方向性，触发PCNA单泛素化，并促进易错聚合酶-eta向染色质的募集。重要的是，ncMMR不限于B细胞，也发生在其他细胞类型中。此外，它有助于由烷化剂诱导的诱变。因此，ncMMR的激活可能在基因组不稳定性和癌症中起作用。
Mismatch repair (MMR) is a key antimutagenic process that increases the fidelity of DNA replication and recombination. Yet genetic experiments showed that MMR is required for antibody maturation, a process during which the immunoglobulin loci of antigen-stimulated B cells undergo extensive mutagenesis and rearrangements. In an attempt to elucidate the mechanism underlying the latter events, we set out to search for conditions that compromise MMR fidelity. Here, we describe noncanonical MMR (ncMMR), a process in which the MMR pathway is activated by various DNA lesions rather than by mispairs. ncMMR is largely independent of DNA replication, lacks strand directionality, triggers PCNA monoubiquitylation, and promotes recruitment of the error-prone polymerase-eta to chromatin. Importantly, ncMMR is not limited to B cells but occurs also in other cell types. Moreover, it contributes to mutagenesis induced by alkylating agents. Activation of ncMMR may therefore play a role in genomic instability and cancer.