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.

SYCP 3使BRCA 2失活，增加基因组不稳定的风险 基因组的不稳定性会增加患癌症的风险。在各种类型的DNA损伤中，DNA双链 断裂（DSB）可以通过其诱导基因组重排的潜力来驱动基因组不稳定性。同源 重组（HR）的功能是准确修复DSB并帮助维持基因组完整性。BRCA 2是一个中心 HR蛋白和募集其他蛋白质，如体细胞中的RAD 51和生殖系细胞中的RAD 51和DMC 1 参与HR的两个特征步骤：1）同源性搜索和2）DNA链侵入。BRCA 2缺失 乳腺癌、卵巢癌和其他癌症的风险增加。机制， BRCA 2的功能，而不是杂合性丢失尚未确定。我的研究解决了这一差距， 并定义了一种新的机制，通过这种机制，生殖系蛋白SYCP 3在体细胞中的错误表达， 细胞抑制BRCA 2介导的HR。 SYCP 3是减数分裂特异性联会复合体的重要结构成分， 减数分裂过程中的染色体分离和重组。SYCP 3通常仅在 生殖系细胞（例如，在睾丸、卵巢中），但在体细胞中不存在。新出现的证据表明SYCP 3是 SYCP 3在某些癌细胞和原发性肿瘤中错误表达，因此SYCP 3被称为癌症/睾丸癌基因。 抗原的SYCP 3在减数分裂中的作用已被较好地理解，但对其潜力了解不多 对体细胞的影响。在生殖系细胞中，SYCP 3和BRCA 2都存在，它们一起起作用， 正常HR介导的减数分裂DSB修复，但SYCP 3在体细胞中的表达导致DNA修复 缺损最近，有报道称，在体细胞中，SYCP 3与BRCA 2相互作用并损害BRCA 2的募集。 RAD 51涉及的机制仍有待确定。我的工作模型是：（1）在生殖细胞中，SYCP 3 促进BRCA 2和DMC 1的相互作用，从而使HR;（2）在体细胞中，SYCP 3限制了BRCA 2和DMC 1的相互作用， BRCA 2和RAD 51的相互作用，从而破坏HR。我的假设是，SYCP 3调节 BRCA 2与RAD 51和DMC 1的差异相互作用。 具体目标1将建立SYCP 3导致BRCA 2功能丧失的生化机制， 通过使用纯化的蛋白质的体外测定，具体目标2将使用基于细胞的模型来确定 SYCP 3和BRCA 2之间的相互作用对HR效率和对 遗传毒性应激 这项提议的发现将确定SYCP 3在体细胞中错误表达的机制。 导致BRCA 2功能缺陷。这些发现将确立SYCP 3在肿瘤中的表达作为一种潜在的 HR缺陷的生物标志物，这也将使患者能够接受癌症治疗，如聚（ADP-核糖） 聚合酶抑制剂