DNA lesions involved in chemotherapy responses and their repair

人类基因组的完整性不断受到来自正常代谢产物的自发DNA损伤的威胁，例如DNA氧化，或环境诱变剂和致癌物如UV光。DNA损伤修复不当是导致癌症发生的主要因素。为了防止这种情况，人类细胞有许多专门的DNA修复机制，以最好的方式修复不同的病变。因此，DNA修复基因的突变会导致癌症风险增加。癌症相关DNA修复基因突变的常见例子包括BRCA 1和BRCA 2乳腺癌基因，以及家族性非息肉病性结直肠癌中突变的MLH 1基因。我们已经确定了一种新的人类DNA修复蛋白，称为ASCIZ，其功能类似于BRCA 1和BRCA 2，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，与BRCA 1-BRCA 2相比，ASCIZ在响应不同类型的DNA损伤时执行此功能，并与MLH 1蛋白协同作用。在这里，我们想研究ASCIZ修复的特定DNA损伤是什么，我们想确定修复是否涉及利用完整基因作为修复模板的复制机制。此外，我们希望产生ASCIZ基因突变的动物，作为研究其在人类癌症发展中作用的模型。缺乏ASCIZ的细胞对DNA损伤剂非常敏感，这些损伤剂类似于临床使用的化疗药物。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。

The integrity of the human genome is constantly threatened by spontaneous DNA damage from products of normal metabolism, for example DNA oxidation, or environmental mutagens and carcinogens such as UV light. Improperly repaired DNA damage is a major contributing factor to the onset of cancer. To prevent this, human cells have a multitude of specialised DNA repair mechanisms to repair distinct lesions in the best possible way. As a consequence, mutations in DNA repair genes lead to increased cancer risk. Common examples for cancer-associated DNA repair gene mutations include the BRCA1 and BRCA2 breast cancer genes, and the MLH1 gene mutated in familial non-polyposis colorectal cancer. We have identified a novel human DNA repair protein termed ASCIZ that performs a function similar 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, compared to BRCA1-BRCA2, ASCIZ performs this function in response to different types of DNA damage and acts in concert with the MLH1 protein. Here we want to investigate what the specific DNA lesions are that are repaired by ASCIZ, and we want to determine if the repair involves a copy mechanism that utilises intact genes as repair templates. In addition, we want to generate animals in which the ASCIZ gene is mutated, as a model to study its role in cancer development in humans. Cells that lack ASCIZ are 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 efficiently.