The role of the BRCA1 and BRCA2 gene in the pathogenesis

BRCA1和BRCA2基因在发病机制中的作用

• 批准号: 7315995
• 负责人: Lawrence C Brody
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7315995
• 关键词: role; BRCA1; BRCA2; gene; pathogenesis

Research in the Molecular Pathogenesis is focused on defining changes in the genes that underlie inherited susceptibilities to common diseases such as cancer and birth defects. Currently under investigation are the inherited breast and ovarian cancer genes, BRCA1 and BRCA2. The biological function of these proteins is currently unknown. Previously, we discovered which proteins specifically interact with BRCA1. We also have found that BRCA1 is important for controlling the expression of other genes and is plays a role in DNA repair. Recent experiments has revealed that BRCA1 appears to help in the process of recognizing and eliminating cells that may progress to form tumors. We now know that the increase in breast, ovarian and prostate cancer risk associated with genetic variants in these genes is due to a failure of these mutated proteins to function in the DNA repair pathway. We used yeast cells as an experimental model to test the functional consequences of mutations found in humans. We have also developed a system for identifying proteins that interact with BRCA1. It is also known that BRCA1 acts to transfer the protein ubiquitin onto other proteins. Through this action BRCA1 may be transferring a signal to start the DNA repair process. The identity of the protein to which this transfer occurs is unknown. We plan to identify these target proteins. We developed two systems capable of measuring this activity of BRCA1. These systems are now being used to identify specific proteins involved in breast tumor formation. During the past year we have been carrying out experiments using tagged ubiquitin expression constructs. These experiments have been successful in that we are able to follow the fate of the ubiquitin as it transferred to target proteins. To date, no BRCA1/BARD1 speciific substrates have been identified. We now plan to carry out subcellular fractionation enrich for BARD1/BRCA1 By tracking and identifying the proteins that serve a a substrate for BRCA1 we should be able to determine the exact role of BRCA1 in DNA repair.An increased understanding of the BRCA1 and BRCA2 genes will lead to improved diagnostic procedures and possible preventative therapies. In the past we applied a bioinformatics approach to probe the role that genomic structure may play in protein evolution. The study of the BRCA1 and BRCA2 genes has led us to discover a new connection between a specific type of gene structure and evolutionary rates of changes. This observation appears to be generalizable to almost any gene and holds true across all metazoan lineages. We recently completed the student of all the exons in each of six genomes. The "rules" we observed for our smaller sample have been confirmed in this larger set.

分子发病机理中的研究集中在定义基因的变化，这些基因是遗传性疾病（例如癌症和先天缺陷）的敏感性的基因的变化。目前正在研究的是遗传性的乳腺癌和卵巢癌基因BRCA1和BRCA2。这些蛋白质的生物学功能目前尚不清楚。以前，我们发现了哪些蛋白质与BRCA1专门相互作用。我们还发现，BRCA1对于控制其他基因的表达很重要，并且在DNA修复中起作用。最近的实验表明，BRCA1似乎有助于识别和消除可能形成肿瘤的细胞的过程。我们现在知道，这些基因中与遗传变异有关的乳腺，卵巢和前列腺癌风险的增加是由于这些突变蛋白在DNA修复途径中起作用。我们使用酵母细胞作为实验模型来测试人类突变的功能后果。我们还开发了一个用于识别与BRCA1相互作用的蛋白质的系统。 众所周知，BRCA1起作用将蛋白质泛素转移到其他蛋白质上。通过这种动作，BRCA1可以传输信号以启动DNA修复过程。这种转移发生的蛋白质的身份尚不清楚。我们计划识别这些靶蛋白。我们开发了两个能够测量BRCA1活动的系统。这些系统现在用于鉴定参与乳腺肿瘤形成的特定蛋白质。在过去的一年中，我们一直使用标记的泛素表达构建体进行实验。这些实验已经成功，因为我们能够遵循泛素转移到靶蛋白的命运。迄今为止，尚未确定BRCA1/BARD1特定基材。现在，我们计划对Bard1/brca1进行亚细胞分级。 通过跟踪和识别为BRCA1提供底物的蛋白质，我们应该能够确定BRCA1在DNA修复中的确切作用。对BRCA1和BRCA2基因的了解增加将导致改善诊断程序和可能的预防疗法。 过去，我们采用了一种生物信息学方法来探测基因组结构在蛋白质进化中的作用。对BRCA1和BRCA2基因的研究使我们发现了特定类型的基因结构与变化的进化速率之间的新联系。这种观察似乎几乎可以推广到任何基因，并且在所有后生谱系中都具有真实性。我们最近完成了六个基因组中每个外显子的学生。我们观察到的较小样本的“规则”已在此较大的集合中得到了证实。