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

APOBEC 对 DNA 复制、ATR 检查点和癌症治疗的影响

• 批准号: 10152561
• 负责人: Lee Zou
• 金额: $ 37.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152561
• 关键词: ATR checkpoint; Aneuploidy; Animal Model; Biochemical; Biological; Cell Cycle; Cell Cycle Regulation; Cell Line; Cells; Chemicals; Chromosome Deletion; Cytosine deaminase; DNA Damage; DNA Repair; DNA biosynthesis; DNA replication fork; Defect; Event; Feedback; Genomic Instability; Genomics; Malignant Neoplasms; Mediating; Mutation; Oncogenic; Pharmaceutical Preparations; Phosphotransferases; Play; Process; Proteins; Site; Source; Stress; Testing; Therapeutic; biological adaptation to stress; cancer cell; cancer genomics; cancer therapy; cancer type; checkpoint therapy; driver mutation; efficacy testing; experience; improved; inhibitor/antagonist; mouse model; novel therapeutic intervention; replication stress; targeted treatment; tumor; tumorigenesis

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.

项目摘要 基因组不稳定是癌症的标志。癌细胞中基因组的不稳定性有多种来源， 例如细胞周期控制、DNA复制和DNA修复中的缺陷。最近的癌症基因组学研究 揭示了不同癌症中的突变特征是不同的，反映了不同类型的致癌基因。 癌细胞在肿瘤发生过程中所经历的压力。特别是， 与APOBEC 3A/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蛋白是癌症亚组中突变的重要驱动因素。有趣的是， 最近的研究表明，APOBEC 3A/B蛋白可能在DNA复制过程中作用于滞后链 复制叉，提出了一个问题，是否APOBECs诱导癌细胞的复制应激。在我们 在初步研究中，我们发现APOBEC 3A/B，通过它们的胞嘧啶脱氨酶活性， 在癌细胞中诱导独特类型的复制应激并激活ATR介导的复制应激 反应此外，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APOBECs施加了一种独特类型的“增变因子”， 在癌细胞中的“驱动”复制应激，其使得癌细胞具有高APOBEC活性 易受ATR抑制。在我们提出的研究中，我们将系统地研究APOBECs如何诱导 复制压力，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 靶向癌细胞中独特的APOBEC应激。这些研究的完成可能会提供一个新的视角， 癌细胞中复制应激，并带来了一种新的治疗策略， 几种癌症类型的治疗。