Regulation and assembly of nuclear DNA repair centres

DNA修复基因的遗传缺陷与人类癌症风险增加有关。例如，BRCA 1和BRCA 2基因突变是家族性乳腺癌最常见的病因，MLH 1基因突变是家族性非息肉病性结直肠癌最常见的病因。我们已经确定了一种新的人类DNA修复蛋白，称为ASCIZ，其功能与BRCA 1和BRCA 2相似，因为它调节细胞核中特定DNA修复中心的RAD 51修复蛋白的浓度。然而，ASCIZ在响应于不同于BRCA 1-BRCA 2的不同类型的DNA损伤时执行该功能，并且它与MLH 1蛋白协同作用。在这里，我们想研究ASCIZ如何调节DNA修复中心的组装，以及它是否在BRCA 1-BRCA 2蛋白的支持下这样做。我们还想知道，当RAD 51蛋白不在修复中心时，它的DNA修复功能是否会减弱，我们还想确定参与这一过程的新蛋白质。我们的初步数据表明，缺乏ASCIZ的细胞对DNA损伤剂变得非常敏感，这些损伤剂与临床使用的化疗药物相似。我们希望我们的研究可以确定开发针对ASCIZ和相关蛋白的药物的可能方法，以便更有效地杀死癌细胞。

Genetic defects in DNA repair genes are associated with increased cancer risk in humans. For example, BRCA1 and BRCA2 gene mutations are the most common causes of familial breast cancer, and MLH1 gene mutations are the most common cause of familial non-polyposis colorectal cancer. We have identified a novel human DNA repair protein termed ASCIZ that performs a similar function to BRCA1 and BRCA2 in that it regulates the concentration of the RAD51 repair protein in specific DNA repair centres in the cell nucleus. However, ASCIZ performs this function in response to different types of DNA damage than BRCA1-BRCA2, and it acts in concert with the MLH1 protein. Here we want to study how ASCIZ regulates the assembly of DNA repair centres, and if it does so with support by the BRCA1-BRCA2 proteins. We also want to know if DNA repair functions of the RAD51 protein are diminished when it is not located in repair centres, and we want to identify novel proteins involved in this process. Our preliminary data show that cells that lack ASCIZ become dramatically hypersensitive to DNA damaging agents that are similar to clinically used chemotherapy drugs. We hope that our studies may identify possible approaches to develop drugs against ASCIZ and related proteins in order to kill cancer cells more effectively.