X连锁基因产物调控BRCA1的作用机制及其与乳腺癌发生的关系

The tumorigenesis of breast cancer is closely associated with X chromosome abnormality and the mutation, haploinsufficiency or loss of function of BRCA1 tumor suppressor. The underlying molecular mechanisms are unclear. Recently we identified that some X-linked gene products can interact and negatively regulate BRCA1 or its partner BARD1, suggesting that X chromosome is an important source for BRCA1/BARD1 regulators. These X-linked BRCA1 regulating genes could be deregulated when Xi chromosome is aberrantly activated under oncogenic stress, leading to loss or insufficiency of BRCA1 and hence compromised DNA damage repair functions, which in turn could promote genomic instability and tumorigenesis of breast cancer. In this proposal, we aimed to: i) identify and characterize novel BRCA1 or BARD1 regulators linked to X chromosomes; and to investigate the mechanism by which they regulate BRCA1; ii) investigate the function of BRCA1 regulators and their role in the pathogenesis of breast cancer. This study will identify novel X-linked BRCA1/BARD1 regulator genes and their role in the initiation and progression of breast cancer, and elucidate the mechanism on how BRCA1 is regulated. It will also provide novel insight into our understanding of the relationship between X chromosome activation status and BRCA1 in the pathogenesis of breast cancer. This study will have important implications in the prevention, treatment of breast cancer as well as in the development of novel antitumor drugs.

X染色体异常、乳腺癌抑癌基因BRCA1的突变、表达下降或缺失与乳腺癌发生密切相关，但是分子机制并不清楚。近期我们研究发现，一些X染色体连锁基因产物是重要的BRCA1或BARD1的调控因子，在X染色体异常（如Xi重新激活和Xa复制）时可异常表达，导致BRCA1水平不足或缺失，促进乳腺癌的发生。本项目拟筛选X染色体基因以便分离鉴定BRCA1负性调控因子，揭示其调控BRCA1的分子机制，并探索其在乳腺癌发生发展中的作用。该研究对于分离新的乳腺癌相关基因、揭示BRCA1的调控机制、阐明X染色体与乳腺癌发生的内在关系以及乳腺癌的防治和抗癌药物研发都具有重要意义。

X染色体异常、乳腺癌抑癌基因BRCA1的突变、表达下降或缺失与乳腺癌发生密切相关，但是分子机制并不清楚。项目“X连锁基因调控BRCA1的作用机制及其与乳腺癌发生的关系（81772953）”旨在分离和鉴定X染色体连锁的调控乳腺癌抑癌蛋白BRCA1的因子，探索其参与乳腺癌发生的作用和机制。这里我们总结项目自实施以来研究的内容、研究结果和取得的重要发现及其意义。项目根据研究计划筛选到两个X染色体连锁基因DCAF8L1和DCAF8L2，并分别探索了它们对BRCA1和BARD1的稳定性的作用和分子机制。项目还进一步研究了X染色体活化与DCAF8L1、DCAF8L2基因表达，以及与乳腺癌发生发展的关系。研究发现，DCAF8L1是可以与BRCA1和BARD1相互作用，并对后二者进行泛素化修饰，促进BRCA1、BARD1的蛋白酶体降解；X染色体的异常和激活可能与DCAF8L1的表达相关，在参与乳腺癌的发生中发挥重要作用。与DCAFL1不同，DCAF8L2只与BARD1相互作用，通过泛素化修饰参与BARD1的蛋白酶体降解，从而间接影响BRCA1的稳定性。上述研究结果表明，X染色体连锁基因DCAF8L1和DCAF8L2是重要的BRCA1或BARD1的调控因子，在X染色体异常（如Xi重新激活和Xa复制）时可异常表达，导致BRCA1和/或BARD1水平不足或缺失，促进乳腺癌的发生。本研究揭示了BRCA1和BARD1蛋白质稳定性调控的分子机制及其与乳腺癌发生的关系。该研究对于分离新的乳腺癌相关基因、揭示BRCA1的调控机制、阐明X染色体与乳腺癌发生的内在关系以及乳腺癌的防治和抗癌药物研发都具有重要意义。

内容获取失败，请点击重试