人类起源识别复合物的最小亚单位hOrc6在DNA复制进程中起重要作用，同时在S期期间在错配修复中（MMR）发挥重要作用。然而，关于hOrc6如何调节DNA复制和DNA损伤响应的分子细节仍需阐明。Orc6水平会在特定类型的基因毒性压力下升高，并且在Thr229处被磷酸化，主要发生在S期期间，以应对氧化压力。包括MMR在内的许多修复途径介导氧化DNA损伤的修复。MMR缺陷与Lynch综合症有关，这会使患者易患许多癌症，包括结肠癌。Orc6水平已知会升高在结肠癌中。有趣的是，肿瘤细胞与相邻正常黏膜相比，显示出降低的hOrc6-Thr229磷酸化水平。此外，野生型和磷酸化死亡形式的Orc6表达升高会导致肿瘤形成能力增加，暗示在“检查点”信号缺失的情况下，细胞会不受限制地增殖。基于这些结果，我们提出，S期中DNA损伤诱导的hOrc6-pThr229磷酸化有助于ATR信号在S期中被激活，停滞叉的推进，并使修复因子组装起来以介导有效的修复，以预防肿瘤形成。我们的研究为hOrc6如何调节基因组稳定性提供了新的见解。

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.