Regulation of APOBEC3 cytidine deaminase-induced mutation during cancerdevelopment

癌症发展过程中 APOBEC3 胞苷脱氨酶诱导突变的调控

基本信息

批准号：
10880034
负责人：
STEVEN A ROBERTS
金额：
$ 39.05万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-06 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10880034
关键词：
Affect BRCA1 Protein BRCA1 gene BRCA2 gene Base Excision Repairs Base Sequence Bioinformatics Breast Cancer Cell Breast Cancer cell line Bypass Cancer Etiology Cell Culture Techniques Cell physiology Cells Cytidine Deaminase DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA biosynthesis DNA replication fork Defect Deletion Mutation Deoxyuridine Development Double Strand Break Repair Drug resistance Enzymes Etiology Evolution Excision Family Family member Frequencies Genetic Heterogeneity Genetic Recombination Genetic Transcription Genomics Human Human Cell Line Induced Mutation Insertion Mutation Malignant Neoplasms Measures Mediating Mutagenesis Mutate Mutation Oncogenes Pathway interactions Patient-Focused Outcomes Patients Proteins Regulation Relapse Role Signal Pathway Site Source System Therapeutic Trans-Activators Transcriptional Activation Tumor Suppressor Genes Ubiquitin Up-Regulation Virus Yeasts base brca gene clinical application homologous recombination insertion/deletion mutation insight mRNA Expression malignant breast neoplasm member multicatalytic endopeptidase complex neoplastic cell posttranscriptional repaired targeted treatment therapeutic development therapeutic target transcription factor tumor tumor progression tumorigenesis

项目摘要

Abstract APOBEC signature mutations (C to T and C to G substitutions in TCA and TCT trinucleotide sequences) comprise the second most abundant mutation signature in human cancers. This signature is caused by aberrant activity of several members of the APOBEC family of cytidine deaminases, which normally function in many cellular processes including the restriction of viruses. Recently, we found that APOBEC3A (A3A) expression is elevated in APOBEC-mutated breast cancer cell lines, resulting in increased cellular cytidine deaminase activity and breast cancer mutagenesis. The objectives of this proposal are to characterize newly identified components of the APOBEC mutation signature, determine how A3A mRNA expression is upregulated in cancer, define proteasomal controls on A3A protein abundance, and characterize DNA repair pathways that limit A3A mutagenesis. Aim1 will determine the causes and consequences of A3A- and APOBEC3B-induced insertion/deletion mutations. Aim 2 will characterize the mechanisms leading to aberrant up-regulation of A3A in breast cancers by identifying the transcription factors and signaling pathways responsible for increasing A3A expression. Additionally, we will investigate the mechanism(s) leading to proteasome-dependent degradation of A3A and assess the mutagenic consequences of defective post- translational control of A3A abundance. Aim3 will characterize anti-mutagenic roles of the homologous recombination proteins BRCA1 and BRCA2 in template switch-mediated bypass of A3A-dependent abasic sites at replication forks. We will determine whether BRCA1 or BRCA2-deficiency elevates APOBEC-induced mutation in human cell lines and genetically define additional proteins involved in the pathway. Successful completion of these aims will enhance our understanding of A3A regulation and its role in cancer etiology. Additionally, these efforts will identify means to limit APOBEC-induced mutagenesis, which could provide therapeutic benefit by limiting continued tumor evolution that leads to drug resistance.

抽象的 APOBEC 特征突变（TCA 和 TCT 三核苷酸中的 C 到 T 和 C 到 G 替换序列）包含人类癌症中第二丰富的突变特征。这个签名是由胞苷脱氨酶 APOBEC 家族的几个成员的异常活性引起，这些成员通常在许多细胞过程中发挥作用，包括限制病毒。最近，我们发现APOBEC3A (A3A) 表达在 APOBEC 突变的乳腺癌细胞系中升高，导致细胞胞苷脱氨酶活性和乳腺癌诱变。该提案的目标是描述新鉴定的 APOBEC 突变特征成分，确定 A3A mRNA 表达情况在癌症中上调，定义蛋白酶体对 A3A 蛋白丰度的控制，并表征 DNA 修复限制 A3A 突变的途径。 Aim1将确定A3A-和的原因和后果 APOBEC3B 诱导的插入/缺失突变。目标 2 将描述导致异常的机制通过鉴定转录因子和信号通路来上调乳腺癌中 A3A 负责增加 A3A 的表达。此外，我们将调查导致的机制 A3A 的蛋白酶体依赖性降解并评估缺陷后的诱变后果 A3A 丰度的翻译控制。 Aim3 将表征同源物的抗突变作用模板开关介导的 A3A 依赖性脱碱基旁路中的重组蛋白 BRCA1 和 BRCA2 位于复制叉的位点。我们将确定 BRCA1 或 BRCA2 缺陷是否会导致 APOBEC 诱导的症状升高人类细胞系的突变并从基因上定义了参与该途径的其他蛋白质。成功的完成这些目标将增强我们对 A3A 调控及其在癌症病因学中的作用的理解。此外，这些努力将确定限制 APOBEC 诱导突变的方法，这可以提供通过限制导致耐药性的持续肿瘤进化来获得治疗益处。