DNA Damage-Induced, S-Phase Specific Phosphorylation of Orc6 is Critical for the Maintenance of Genome Stability
DNA Damage-Induced, S-Phase Specific Phosphorylation of Orc6 is Critical for the Maintenance of Genome Stability
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DOI：
10.1080/10985549.2023.2196204
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发表时间：
2023-04
影响因子：
5.3
通讯作者：
Yo-Chuen Lin;Dazhen Liu;Arindam Chakraborty;V. Macias;Eileen Brister;Jay Sonalkar;Linyuan Shen;Jaba Mitra;T. Ha;A. Kajdacsy-Balla;K. Prasanth;S. Prasanth
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作者：
Yo-Chuen Lin;Dazhen Liu;Arindam Chakraborty;V. Macias;Eileen Brister;Jay Sonalkar;Linyuan Shen;Jaba Mitra;T. Ha;A. Kajdacsy-Balla;K. Prasanth;S. Prasanth
人类起源识别复合物的最小亚基hOrc 6是DNA复制过程所必需的，在S期错配修复（MMR）中起着重要作用。然而，hOrc 6如何调节DNA复制和DNA损伤反应的分子细节仍有待阐明。Orc 6水平在特定类型的遗传毒性应激后升高，并且其在Thr 229处磷酸化，主要在S期期间，响应于氧化应激。许多修复途径，包括MMR，介导氧化DNA损伤修复。MMR的缺陷与林奇综合征有关，使患者易患许多癌症，包括结肠直肠癌。已知orc 6水平在结直肠癌中升高。有趣的是，与邻近的正常粘膜相比，肿瘤细胞显示降低的hOrc 6-Thr 229磷酸化。此外，Orc 6的野生型和磷酸化死亡形式的表达升高导致致瘤性增加，这意味着在不存在该“检查点”信号的情况下，细胞增殖不减弱。基于这些结果，我们提出，DNA损伤诱导的hOrc 6-pThr 229磷酸化在S期促进ATR信号在S期，停止叉进展，并使组装修复因子介导有效的修复，以防止肿瘤发生。我们的研究为hOrc 6如何调节基因组稳定性提供了新的见解。
Abstract The smallest subunit of the human Origin Recognition Complex, hOrc6, is required for DNA replication progression and plays an important role in mismatch repair (MMR) during S-phase. However, the molecular details of how hOrc6 regulates DNA replication and DNA damage response remain to be elucidated. Orc6 levels are elevated upon specific types of genotoxic stress, and it is phosphorylated at Thr229, predominantly during S-phase, in response to oxidative stress. Many repair pathways, including MMR, mediate oxidative DNA damage repair. Defects in MMR are linked to Lynch syndrome, predisposing patients to many cancers, including colorectal cancer. Orc6 levels are known to be elevated in colorectal cancers. Interestingly, tumor cells show reduced hOrc6-Thr229 phosphorylation compared to adjacent normal mucosa. Further, elevated expression of wild-type and the phospho-dead forms of Orc6 results in increased tumorigenicity, implying that in the absence of this “checkpoint” signal, cells proliferate unabated. Based on these results, we propose that DNA-damage-induced hOrc6-pThr229 phosphorylation during S-phase facilitates ATR signaling in the S-phase, halts fork progression, and enables assembly of repair factors to mediate efficient repair to prevent tumorigenesis. Our study provides novel insights into how hOrc6 regulates genome stability.