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。

基本信息

  • 批准号:
    10606951
  • 负责人:
  • 金额:
    $ 0.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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风险 基因组不稳定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的不稳定性。同源 重组(HR)的功能是准确修复DSB并帮助维持基因组的完整性。BRCA2是一个中心 HR蛋白和募集其他蛋白,如体细胞中的RAD51和生殖细胞中的RAD51和DMC1 参与HR的两个标志性步骤:1)同源搜索和2)DNA链侵袭。BRCA2的丢失 功能与患乳腺癌、卵巢癌和其他癌症的风险增加有关。停用的机制 除杂合性缺失外,BRCA2的功能还有待确定。我的研究解决了这一差距 了解并确定胚系蛋白SYCP3在体细胞中错误表达的新机制 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,是 减数分裂过程中的适当重组和染色体分离。SYCP3通常仅在 生殖细胞(例如,在睾丸、卵巢中),但不在体细胞中。新出现的证据表明SYCP3是 在某些癌细胞和原发肿瘤中错误表达,因此SYCP3被称为癌症/睾丸 抗原。SYCP3在减数分裂中的作用相对较好,但对其潜在的了解还不是很多 对体细胞的影响。在生殖系细胞中,SYCP3和BRCA2都存在,它们共同作用于 减数分裂DSB的正常HR介导的修复,但SYCP3在体细胞中的表达导致DNA修复 叛逃。最近,据报道,在体细胞中,SYCP3与BRCA2相互作用,并损害 RAD51涉及有待定义的机制。我的工作模型是:(1)在生殖系细胞中,SYCP3 促进BRCA2和DMC1的相互作用,从而使HR;(2)在体细胞中,SYCP3限制 BRCA2和RAD51的相互作用从而扰乱HR。我的假设是SYCP3调节 BRCA2与RAD51和DMC1的差异相互作用 特异性目标1将建立SYCP3导致BRCA2功能丧失的生化机制 用纯化的蛋白质进行体外体细胞鉴定。特定目标2将使用基于细胞的模型来确定 SYCP3和BRCA2相互作用对HR效率和对 基因毒性应激。 这项研究的发现将确定SYCP3在体细胞中错误表达的机制 导致BRCA2功能缺陷。这一发现将确定SYCP3在肿瘤中的表达是一种潜在的 HR缺乏的生物标记物,这也将使患者能够接受像Poly(ADP-核糖)这样的癌症治疗 聚合酶抑制剂。

项目成果

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Ash Jay其他文献

Ash Jay的其他文献

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{{ truncateString('Ash Jay', 18)}}的其他基金

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:
    10213669
  • 财政年份:
    2018
  • 资助金额:
    $ 0.25万
  • 项目类别:
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:
    9763325
  • 财政年份:
    2018
  • 资助金额:
    $ 0.25万
  • 项目类别:

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