The role of the BRCA1 and BRCA2 gene in the pathogenesis

分子发病机制的研究重点是定义基因的变化，这些变化是遗传对常见疾病（如癌症和出生缺陷）的易感性的基础。目前正在研究的是遗传性乳腺癌和卵巢癌基因BRCA 1和BRCA 2。这些蛋白质的生物学功能目前尚不清楚。之前，我们发现了哪些蛋白质与BRCA 1特异性相互作用。我们还发现BRCA 1对控制其他基因的表达很重要，并在DNA修复中发挥作用。最近的实验表明，BRCA 1似乎有助于识别和消除可能形成肿瘤的细胞。我们现在知道，与这些基因中的遗传变异相关的乳腺癌、卵巢癌和前列腺癌风险的增加是由于这些突变的蛋白质在DNA修复途径中无法发挥作用。我们使用酵母细胞作为实验模型来测试在人类中发现的突变的功能后果。我们还开发了一个系统，用于识别与BRCA 1相互作用的蛋白质。 还已知BRCA 1可将蛋白质泛素转移到其他蛋白质上。通过这种作用，BRCA 1可能会传递一个信号来启动DNA修复过程。这种转移发生的蛋白质的身份是未知的。我们计划鉴定这些靶蛋白。我们开发了两种能够测量BRCA 1活性的系统。这些系统现在被用于识别参与乳腺肿瘤形成的特定蛋白质。在过去的一年里，我们一直在进行实验，使用标记的泛素表达结构。这些实验是成功的，因为我们能够跟踪泛素转移到靶蛋白的命运。迄今为止，尚未鉴定出BRCA 1/BARD 1特异性底物。我们现在计划进行BARD 1/BRCA 1的亚细胞分级富集 通过追踪和鉴定作为BRCA 1底物的蛋白质，我们应该能够确定BRCA 1在DNA修复中的确切作用。对BRCA 1和BRCA 2基因的进一步了解将导致改进的诊断程序和可能的预防性治疗。 在过去，我们应用生物信息学方法来探测基因组结构在蛋白质进化中可能发挥的作用。对BRCA 1和BRCA 2基因的研究使我们发现了一种特定类型的基因结构与进化变化率之间的新联系。这一观察结果似乎可以推广到几乎任何基因，并适用于所有后生动物谱系。我们最近完成了六个基因组中所有外显子的学生。我们在小样本中观察到的“规则”在这个大样本中得到了证实。

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.