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.

项目概要 基因组不稳定性是癌症的一个标志，癌细胞中的基因组不稳定性有多种来源。 例如最近的癌症基因组学研究发现了细胞周期控制、DNA 复制和 DNA 修复中的缺陷。 研究表明，不同癌症的突变特征是不同的，反映了不同类型的致癌因素 强调癌细胞在肿瘤发生过程中所经历的，特别是突变。 与 APOBEC3A/B 胞嘧啶脱氨酶相关的特征在多种癌症类型中普遍存在， 表明这些 APOBEC 蛋白是一部分癌症突变的重要驱动因素。 最近的研究表明 APOBEC3A/B 蛋白可能在 DNA 复制过程中在滞后链上发挥作用 复制叉，提出了一个问题：APOBEC 是否会在癌细胞中诱导复制应激。 初步研究，我们发现证据表明 APOBEC3A/B 通过其胞嘧啶脱氨酶活性， 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 此外，我们发现具有高 APOBEC 活性的癌细胞对这种反应越来越敏感。 ATR 抑制。这些发现使我们认识到 APOBEC 会施加一种独特的“突变体”。 癌细胞中驱动的“复制压力”，使癌细胞具有高 APOBEC 活性 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，以及我们如何具体 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观点。 癌细胞的复制压力，并带来一种新的治疗策略，可以显着改善 几种癌症类型的治疗。