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灭活BRCA2增加了基因组不稳定性的风险 基因组不稳定性增加了癌症的风险。在不同类型的DNA损伤中，DNA双链 断裂（DSB）可以通过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）功能可准确修复DSB并有助于维持基因组完整性。 BRCA2是中央 HR蛋白并募集其他蛋白质，例如体细胞中的RAD51，种系细胞中的Rad51和DMC1 参与HR的两个签名步骤：1）同源搜索和2）DNA链入侵。损失BRCA2 功能与乳房，卵巢癌和其他癌症的风险增加有关。失活的机制 BRCA2功能以外的杂合性丧失尚未确定。我的研究解决了这个差距 知识并定义了一种新机制 细胞抑制BRCA2介导的HR。 Sycp3是减数分裂特异性突发事件复合物的重要结构成分，是必需的 减数分裂过程中适当的重组和染色体分离。 Sycp3通常仅在 种系细胞（例如，在睾丸，卵巢中），但在体细胞中不。新兴的证据表明sycp3是 在某些癌细胞和原发性肿瘤中脱颖而出，因此Sycp3被称为癌症/睾丸 抗原。 Sycp3在减数分裂中的作用相对众所周知，但对其潜力并不了解 体细胞的作用。在种系细胞中，Sycp3和BRCA2都存在，它们共同起作用 HR介导的减数分裂DSB的正常修复，但Sycp3在体细胞中的表达导致DNA修复 缺点。最近，据报道，在体细胞中，sycp3与BRCA2相互作用，并损害了 RAD51涉及待定的机制。我的工作模型是：（1）在种系细胞中，sycp3 促进BRCA2和DMC1的相互作用，从而使人力资源； （2）在体细胞中，Sycp3限制了 BRCA2和RAD51的相互作用，从而破坏HR。我的假设是Sycp3调节 BRCA2与RAD51和DMC1的差异相互作用。 特定的目标1将建立sycp3导致BRCA2功能损失的生化机制 通过纯化蛋白质在体外测定中进行体外细胞。特定目标2将使用基于单元的模型来确定 Sycp3与BRCA2之间相互作用在人力资源效率上的生物学意义以及对 遗传毒性应激。 该提案的发现将确定体细胞中的Sycp3 misspression的机制 导致BRCA2功能缺陷。这些发现将在肿瘤中建立Sycp3表达作为潜力 人力资源缺乏症的生物标志物，这也将使患者能够进行癌症治疗（ADP-核糖）等癌症治疗剂 聚合酶抑制剂。