Impacts of APOBECs on DNA replication, ATR checkpoint, and cancer therapy

项目摘要 基因组不稳定是癌症的一个标志。癌细胞中的基因组不稳定性有多种来源， 如细胞周期控制、DNA复制和DNA修复方面的缺陷。最近的癌症基因组学研究已经 揭示了不同癌症的突变特征是不同的，反映了不同类型的致癌 癌细胞在肿瘤发生过程中所经历的压力。特别是，突变 与APOBEC3A/B胞嘧啶脱氨酶相关的特征在几种癌症类型中普遍存在， 这表明这些APOBEC蛋白是癌症亚群突变的重要驱动因素。有趣的是， 最近的研究表明，APOBEC3A/B蛋白可能在滞后链上的DNA复制过程中起作用 这引发了一个问题，即APOBEC是否会在癌细胞中诱导复制压力。在我们的 初步研究，我们发现有证据表明，APOBEC3A/B通过胞嘧啶脱氨酶活性， 在癌细胞中诱导一种独特类型的复制应激并激活ATR介导的复制应激 回应。此外，我们发现，具有高APOBEC活性的癌细胞对 ATR抑制。这些发现使我们假设APOBEC施加了一种独特的“突变因子-- 癌细胞中的“驱动”复制压力，使癌细胞具有高APOBEC活性 易受ATR抑制。在我们提议的研究中，我们将系统地研究APOBEC是如何诱导 复制应激，ATR如何抑制APOBEC诱导的基因组不稳定性，以及我们如何特异性地 针对癌细胞中独特的APOBEC应激反应。这些研究的完成可能会提供一个新的视角 癌细胞中的复制压力，并带来一种新的治疗策略，可能会显著改善 几种癌症类型的治疗。

Project Summary Genomic instability is a hallmark of cancer. The genomic instability in cancer cells arises from multiple sources, such as defects in cell-cycle control, DNA replication, and DNA repair. Recent cancer genomics studies have revealed that the mutation signatures in different cancers are distinct, reflecting the different types of oncogenic stress that cancer cells have experienced during the process of tumorigenesis. In particular, the mutation signatures associated with APOBEC3A/B cytosine deaminases are prevalent in several cancer types, suggesting that these APOBEC proteins are important drivers of mutation in a subset of cancers. Interestingly, recent studies have suggested that APOBEC3A/B proteins may act during DNA replication on the lagging strand of replication forks, raising a question as to whether APOBECs induce replication stress in cancer cells. In our preliminary studies, we have found evidence that APOBEC3A/B, through their cytosine deaminase activity, induce a unique type of replication stress in cancer cells and activate the ATR-mediated replication stress response. Furthermore, we found that cancer cells harboring high APOBEC activity are increasingly sensitive to ATR inhibition. These findings have led us to hypothesize that APOBECs impose a unique type of “mutator- driven” replication stress in cancer cells, which renders the cancer cells harboring high APOBEC activity susceptible to ATR inhibition. In our proposed studies, we will systematically investigate how APOBECs induce replication stress, how ATR suppresses the APOBEC-induced genomic instability, and how we can specifically target the unique APOBEC stress in cancer cells. The completion of these studies may provide a new view of the replication stress in cancer cells, and bring about a novel therapeutic strategy that may significantly improve the treatment of several cancer types.