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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Regulation Of Proliferating Cell Nuclear Antigen Ubiquitination In Mammalian Cells
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Regulation Of Proliferating Cell Nuclear Antigen Ubiquitination In Mammalian Cells

机译：哺乳动物细胞中增殖细胞核抗原泛素化的调控

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摘要

After exposure to DNA-damaging agents that block the progress of the replication fork, monoubiquitination of proliferating cell nuclear antigen (PCNA) mediates the switch from replicative to translesion synthesis DNA polymerases. We show that in human cells, PCNA is monoubiquitinated in response to methyl methane-sulfonate and mitomycin C, as well as UV light, albeit with different kinetics, but not in response to bleomycin or camptothecin. Cy-clobutane pyrimidine dimers are responsible for most of the PCNA ubiquitination events after UV-irradiation. Failure to ubiquitinate PCNA results in substantial sensitivity to UV and methyl methane-sulfonate, but not to camptothecin or bleomycin. PCNA ubiquitination depends on Replication Protein A (RPA), but is independent of ATR-mediated checkpoint activation. After UV-irradiation, there is a temporal correlation between the disappearance of the deu-biquitinating enzyme USP1 and the presence of PCNA ubiquitination, but this correlation was not found after chemical mutagen treatment. By using cells expressing photolyases, we are able to remove the UV lesions, and we show that PCNA ubiquitination persists for many hours after the damage has been removed. We present a model of translesion synthesis behind the replication fork to explain the persistence of ubiquitinated PCNA.
机译：暴露于阻断复制叉进程的DNA破坏剂后，增殖细胞核抗原（PCNA）的单泛素化介导了从复制到损伤合成DNA聚合酶的转换。我们显示，在人类细胞中，PCNA是单泛素化的，响应于甲烷磺酸甲酯和丝裂霉素C以及紫外线，尽管具有不同的动力学，但不响应博来霉素或喜树碱。环丁烷嘧啶二聚体是紫外线照射后大部分PCNA泛素化事件的原因。不能泛素化PCNA会导致对UV和甲烷磺酸甲酯的敏感，但对喜树碱或博来霉素不敏感。 PCNA泛素化取决于复制蛋白A（RPA），但独立于ATR介导的检查点激活。紫外线照射后，双泛素化酶USP1的消失与PCNA泛素化之间存在时间相关性，但是在化学诱变剂处理后未发现这种相关性。通过使用表达光裂解酶的细胞，我们能够去除UV损伤，并且我们显示PCNA泛素化作用在去除损伤后会持续许多小时。我们提出复制叉背后的跨病变合成模型，以解释泛素化PCNA的持久性。

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