SYCP3 Inactivates BRCA2 Increasing Risk of Genomic Instability: Misexpression of germ-line protein, SYCP3, in somatic cells causes BRCA2 functional deficiency increasing risk of genomic instability.

SYCP3 使 BRCA2 失活，增加基因组不稳定的风险：体细胞中种系蛋白 SYCP3 的错误表达会导致 BRCA2 功能缺陷，增加基因组不稳定的风险。

• 批准号: 10606951
• 负责人: Ash Jay
• 金额: $ 0.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606951
• 关键词: Address; Affect; Affinity; Alanine; Attention; BRCA deficient; BRCA2 Protein; BRCA2 gene; Binding; Biochemical; Biological; Biological Assay; Biological Markers; Breast; Cancer Patient; Cells; Chromosome Segregation; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Defect; Double Strand Break Repair; Filament; Genetic Recombination; Genome; Genome Stability; Genomic Instability; Genotoxic Stress; Germ Lines; Impairment; In Vitro; Individual; Knowledge; Length; Loss of Heterozygosity; Malignant Neoplasms; Maps; Mediating; Meiosis; Modeling; Molecular; Ovarian; Ovary; Pathway interactions; Patients; Poly(ADP-ribose) Polymerases; Predisposition; Primary Neoplasm; Proteins; Reporter; Reporting; Research; Risk; Role; Scanning; Single-Stranded DNA; Site; Somatic Cell; Synaptonemal Complex; Testing; Testis; Therapeutic; Tumor Suppressor Proteins; base; cancer cell; cancer risk; cancer testis antigen; crosslink; functional loss; genome integrity; high risk; homologous recombination; in vitro Assay; inhibitor; malignant breast neoplasm; mutant; novel; potential biomarker; reconstitution; recruit; repaired; response; tumor

SYCP3 Inactivates BRCA2 Increasing Risk of Genomic Instability Genome instability increases the risk for cancer. Among the diverse types of DNA damage, DNA double stranded breaks (DSBs) can drive genomic instability by their potential to induce genome rearrangements. Homologous recombination (HR) functions to accurately repair DSBs and help maintain genomic integrity. BRCA2 is a central HR protein and recruits other proteins such as RAD51 in somatic cells and RAD51 and DMC1 in germline cells to participate in the two signature steps of HR: 1) Homology search and 2) DNA strand invasion. Loss of BRCA2 function is associated with increased risk of breast, ovarian and other cancers. Mechanisms that inactivate BRCA2 function other than loss of heterozygosity are yet to be determined. My research addresses this gap in knowledge and defines a new mechanism by which misexpression of the germline protein SYCP3 in somatic cells inhibits BRCA2-mediated HR. SYCP3 is an essential structural component of the meiosis-specific synaptonemal complex and is required for proper recombination and chromosome segregation during meiosis. SYCP3 is typically expressed only in germline cells (e.g., in testis, ovary) but not in somatic cells. Emerging evidence indicates that SYCP3 is misexpressed in certain cancer cells and primary tumors, and hence SYCP3 has been termed a cancer/testis antigen. The role of SYCP3 in meiosis is relatively well understood but not much is known about its potential effects in somatic cells. In germline cells, both SYCP3 and BRCA2 are present and they function together for normal HR-mediated repair of meiotic DSBs, but SYCP3 expression in somatic cells results in a DNA repair defect. Recently, it was reported that in somatic cells SYCP3 interacts with BRCA2 and impairs recruitment of RAD51 involving mechanisms that remain to be defined. My working model is that: (1) In germline cells, SYCP3 promotes the interaction of BRCA2 and DMC1 and thereby enables HR; (2) In somatic cells, SYCP3 limits the interaction of BRCA2 and RAD51 and thereby disrupts HR. My hypothesis is that SYCP3 regulates the differential interaction of BRCA2 with RAD51 and DMC1. Specific Aim 1 will establish the biochemical mechanism by which SYCP3 leads to functional loss of BRCA2 in somatic cells by in vitro assays using purified proteins. Specific Aim 2 will use cell based models to determine the biological significance of the interaction between SYCP3 and BRCA2 on HR efficiency and response to genotoxic stress. The findings from this proposal will determine the mechanism by which SYCP3 misexpression in somatic cells leads to BRCA2 functional deficiency. The findings will establish SYCP3 expression in tumors as a potential biomarker for HR deficiency, which will also enable patients for cancer therapeutics like Poly (ADP-ribose) polymerase inhibitors.

SYCP3 使 BRCA2 失活，增加基因组不稳定的风险 基因组不稳定会增加患癌症的风险。在多种类型的 DNA 损伤中，DNA 双链损伤 断裂（DSB）可以通过诱导基因组重排来驱动基因组不稳定。同源 重组 (HR) 的作用是准确修复 DSB 并帮助维持基因组完整性。 BRCA2 是一个中枢 HR 蛋白并招募其他蛋白，例如体细胞中的 RAD51 以及生殖细胞中的 RAD51 和 DMC1 参与HR的两个特征步骤：1）同源性搜索和2）DNA链入侵。 BRCA2 缺失 功能与乳腺癌、卵巢癌和其他癌症的风险增加有关。失活机制 除了杂合性丧失之外，BRCA2 的功能尚未确定。我的研究解决了这一差距 知识并定义了一种新机制，通过该机制，体细胞中种系蛋白 SYCP3 的错误表达 细胞抑制 BRCA2 介导的 HR。 SYCP3 是减数分裂特异性联会复合体的重要结构成分，并且是减数分裂所必需的 减数分裂期间的正确重组和染色体分离。 SYCP3 通常仅表达于 生殖细胞（例如，睾丸、卵巢），但体细胞不存在。新出现的证据表明 SYCP3 SYCP3 在某些癌细胞和原发性肿瘤中错误表达，因此被称为癌症/睾丸 抗原。 SYCP3 在减数分裂中的作用相对较好地了解，但对其潜力知之甚少 对体细胞的影响。在生殖细胞中，SYCP3 和 BRCA2 都存在，并且它们一起发挥作用 正常 HR 介导的减数分裂 DSB 修复，但体细胞中 SYCP3 的表达会导致 DNA 修复 缺点。最近，据报道，在体细胞中 SYCP3 与 BRCA2 相互作用并损害 BRCA2 的募集 RAD51 涉及的机制仍有待定义。我的工作模型是：（1）在生殖细胞中，SYCP3 促进 BRCA2 和 DMC1 的相互作用，从而实现 HR； (2) 在体细胞中，SYCP3限制 BRCA2 和 RAD51 相互作用，从而扰乱 HR。我的假设是 SYCP3 调节 BRCA2 与 RAD51 和 DMC1 的差异相互作用。 具体目标 1 将建立 SYCP3 导致 BRCA2 功能丧失的生化机制 使用纯化蛋白质进行体外测定的体细胞。具体目标 2 将使用基于细胞的模型来确定 SYCP3 和 BRCA2 之间的相互作用对 HR 效率和反应的生物学意义 遗传毒性应激。 该提案的结果将确定体细胞中 SYCP3 错误表达的机制 导致 BRCA2 功能缺陷。这些发现将确立 SYCP3 在肿瘤中的表达作为潜在的 HR 缺陷的生物标志物，这也将使患者能够接受聚（ADP-核糖）等癌症治疗 聚合酶抑制剂。