Molecular Mechanisms of APOBEC-Induced Mutagenesis in Cancer

APOBEC 诱导癌症突变的分子机制

• 批准号: 10737783
• 负责人: Remi Buisson
• 金额: $ 8.17万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737783
• 关键词: Attenuated; Automobile Driving; Binding; Cells; Cessation of life; Clinical; Clinical Treatment; Complex; Cytosine; DNA; DNA Damage; DNA Repair; DNA Sequence Alteration; DNA biosynthesis; Data; Deamination; Development; Disease Progression; Drug resistance; Event; Evolution; Family; Genetic Transcription; Genetic Variation; Genome; Genomic Instability; Genomics; Goals; Heterogeneity; Individual; Induced Mutation; Knowledge; Lead; Location; Malignant Neoplasms; Molecular; Mutagenesis; Mutation; Natural Immunity; Neoplasm Metastasis; Normal Cell; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Population; Process; Prognosis; Proteins; Regulation; Research; Resistance; Sampling; Signal Pathway; Signal Transduction; Single Stranded DNA Virus; Single-Stranded DNA; Site; Source; Stat2 protein; Stress; Survival Rate; System; Technology; Therapeutic; Uracil; Virus Replication; Writing; anticancer research; apoB mRNA editing catalytic subunit; cancer cell; cancer cell differentiation; cancer genome; cancer type; chemotherapy; fighting; genomic signature; insight; member; neoplastic cell; next generation sequencing; prevent; protein complex; replication stress; therapeutic development; tumor; tumor heterogeneity

PROJECT SUMMARY Tumor heterogeneity is the main cause of resistance to current chemotherapy drugs as well as metastasis development, leading to patients' death. Within the same tumor from the same patient, tumor cells might be subtly or even dramatically different, making it harder to treat clinically. Understanding mechanisms driving cancer diversity is a critical step toward developing new strategies to attenuate tumor evolution and adaptation. Genomic instability is a prominent source of genetic diversity within tumors, generating a cell population subject to potential selection from a micro-environmental or therapeutic context. In recent years, next- generation sequencing technologies have begun to identify genomic signatures of DNA damage and errors in DNA repair processes, revealing new mechanisms causing an accumulation of mutations in cancer genomes. From the 30 mutational signatures identified across many cancer types to date, one is particularly dominant: the APOBEC signature. APOBEC3A (A3A) and APOBEC3B (A3B), two members of the APOBEC3 family, target TpC motifs on single-stranded DNA and are the major sources of the APOBEC mutational signature detected in patients' tumor samples. Our preliminary observation identified a discrepancy between A3A and A3B expression and mutation accumulation in cancer cells. On one hand, A3A is rarely found expressed, yet many of the tumors have a strong A3A-mutational signature. On the other hand, A3B is expressed in most cancer cells, but only a fraction has an A3B-mutational signature. Both A3A and A3B significantly increase mutations in tumors, but these observations have led us to propose that A3A and A3B expression is not a reliable way to assess the APOBEC status of cancer cells, as previously thought. We propose that A3A is tightly regulated at the transcription level and transiently expressed to generate mutations. Our study will explain why A3A is rarely found expressed in cancer but many cancers have a strong A3A mutational signature. In contrast, we propose that A3B is regulated at the protein level to protect the genome against A3B activity. Our goal is to uncover the molecular mechanisms that govern A3A and A3B regulation in cancer cells. Our overall hypothesis is that cells exploit two separate mechanisms to regulate A3A and A3B and to protect their genome against their activity. In addition, we propose that specific signals in cancer lead to the deregulation of these protective mechanisms, causing a surge of mutations. Our Specific Aims are to 1) define signaling pathways in cancer cells that regulate A3A expression and 2) identify protein complexes controlling A3B activity in cancer cells. Our long-term goal is to develop therapeutic strategies to suppress mutations in the genome caused by A3A and A3B, leading to tumor heterogeneity, metastasis, and drug resistance.

项目摘要 肿瘤的异质性是导致肿瘤对现有化疗药物耐药和转移的主要原因 发展，导致患者死亡。在同一患者的同一肿瘤中，肿瘤细胞可能 细微甚至显著的不同，使得临床治疗更加困难。理解驱动机制 癌症多样性是发展新策略以减弱肿瘤演变和适应的关键一步。 基因组不稳定性是肿瘤内遗传多样性的一个重要来源， 经受来自微环境或治疗背景的潜在选择。近年来，继- 第二代测序技术已经开始识别DNA损伤和错误的基因组特征， DNA修复过程，揭示了导致癌症基因组突变积累的新机制。 从迄今为止在许多癌症类型中确定的30种突变特征中，有一种特别占主导地位： APOBEC签名。APOBEC 3A（A3 A）和APOBEC 3B（A3 B），APOBEC 3家族的两个成员， 靶向单链DNA上的TpC基序，是APOBEC突变特征的主要来源 在病人的肿瘤样本中检测到。我们的初步观察发现A3 A和 癌细胞中A3 B表达和突变积累。一方面，A3 A很少被发现表达，但 许多肿瘤具有强烈的A3 A突变特征。另一方面，A3 B在大多数 癌细胞，但只有一小部分具有A3 B突变特征。A3 A和A3 B均显著增加 但是这些观察结果使我们提出A3 A和A3 B的表达并不是肿瘤中的一个突变。 这是一种可靠的方法来评估癌细胞的APOBEC状态，正如以前所认为的那样。我们认为A3 A是 在转录水平受到严格调节，并瞬时表达以产生突变。我们的研究将 解释了为什么A3 A很少在癌症中表达，但许多癌症具有强烈的A3 A突变， 签名.相反，我们认为A3 B在蛋白质水平上受到调节，以保护基因组免受A3 B的侵害 活动我们的目标是揭示癌细胞中A3 A和A3 B调控的分子机制。 我们的总体假设是，细胞利用两种不同的机制来调节A3 A和A3 B， 他们的基因组与他们的活动。此外，我们认为癌症中的特定信号导致了 这些保护机制的失调，导致突变激增。我们的具体目标是：（1） 确定癌细胞中调节A3 A表达的信号通路，2）鉴定蛋白复合物 控制癌细胞中的A3 B活性。我们的长期目标是开发治疗策略， 由A3 A和A3 B引起的基因组突变，导致肿瘤异质性、转移和药物依赖性。 阻力