The hMsh2-hMsh6 Complex Acts in Concert with Monoubiquitinated PCNA and Pol η in Response to Oxidative DNA Damage in Human Cells
The hMsh2-hMsh6 Complex Acts in Concert with Monoubiquitinated PCNA and Pol η in Response to Oxidative DNA Damage in Human Cells
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DOI：
10.1016/j.molcel.2011.06.023
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发表时间：
2011-08-19
期刊：
影响因子：
16
通讯作者：
Kannouche, Patricia L.
中科院分区：
文献类型：
--
作者：
Zlatanou, Anastasia;Despras, Emmanuelle;Kannouche, Patricia L.
泛素对 PCNA 的翻译后修饰在协调 DNA 复制过程中的 DNA 损伤耐受过程中发挥着重要作用。 PCNA 的单泛素化可促进复制 DNA 聚合酶与低保真聚合酶 eta (eta) 之间的转换，从而绕过复制过程中紫外线诱导的 DNA 损伤。在这里，我们表明，为了响应氧化应激，PCNA 以不依赖于 S 期和 USP1 的方式短暂地单泛素化。此外，Poleta 通过其 PCNA 结合和泛素结合基序与 mUb-PCNA 在氧化 DNA 损伤位点相互作用。引人注目的是，虽然 PCNA 或 Pol eta 招募到染色质的这种修饰不需要功能性碱基切除修复，但 hMsh2-hMsh6 的存在是必不可少的。我们的研究结果强调了响应氧化 DNA 损伤的替代途径，该途径可能协调去除氧化诱导的成簇 DNA 损伤，并可以解释 MSH2 缺陷细胞中高水平的氧化 DNA 损伤。
Posttranslational modification of PCNA by ubiquitin plays an important role in coordinating the processes of DNA damage tolerance during DNA replication. The monoubiquitination of PCNA was shown to facilitate the switch between the replicative DNA polymerase with the low-fidelity polymerase eta (eta) to bypass UV-induced DNA lesions during replication. Here, we show that in response to oxidative stress, PCNA becomes transiently monoubiquitinated in an S phase- and USP1-independent manner. Moreover, Pol eta interacts with mUb-PCNA at sites of oxidative DNA damage via its PCNA-binding and ubiquitin-binding motifs. Strikingly, while functional base excision repair is not required for this modification of PCNA or Pol eta recruitment to chromatin, the presence of hMsh2-hMsh6 is indispensable. Our findings highlight an alternative pathway in response to oxidative DNA damage that may coordinate the removal of oxidatively induced clustered DNA lesions and could explain the high levels of oxidized DNA lesions in MSH2-deficient cells.