Molecular genetic analysis of BRCT domain function and RhoGEF signalling in DNA-damage response and apoptosis.

癌症是一系列基因变化的结果，通常是DNA的突变。DNA持续暴露于一系列破坏因子中，但大多数突变通过细胞修复机制得到纠正。我们现在知道，如果这些机制正常工作，很少的突变会导致癌症。然而，如果这些DNA损伤修复机制本身有缺陷，就会发生高突变率，导致癌症的风险也很高。DNA损伤还有另一个后果。如果损伤太大，细胞就会自杀，不是因为它不能正常工作，而是因为它感觉到了DNA损伤，选择了死亡。对DNA损伤反应的一个知之甚少的方面是细胞如何感知损伤并激活自杀过程。我们已经发现了一种新的基因，它似乎在这种感知和自杀信号过程中发挥作用。这种基因的小鼠版本本身可以作为一种致癌基因。然而，我们建议研究黑腹果蝇的等效基因，一个更强大的实验系统，以详细描述其在这些过程中的作用。通过这种方式，我们希望能够更详细地了解细胞处理DNA损伤的方式，以及当损伤太严重时选择自杀的方式。

Cancers arise as a consequence of a series of genetic changes, usually by mutation of DNA. DNA is consistently exposed to an array of damaging agents, but the majority of mutations are corrected by cellular repair mechanisms. We now know that if these mechanisms work normally, too few mutations persist for cancer to result. However if these DNA damage repair mechanisms are themselves faulty, a high mutation rate occurs and a high risk of cancer results. DNA damage has another outcome. If the damage is too extensive, the cell commits suicide, not because it cannot function, but because it senses the DNA damage and chooses to die. One poorly understood aspect of the response to DNA damage is how the cell senses the damage and activates the suicide process. We have discovered a novel gene that appears to play a role in this sensing and suicide signalling process. The mouse version of this gene can itself act as a cancer-causing gene. We propose, however, to study the equivalent gene in Drosophila melanogaster, a more powerful experimental system, to characterise in detail its role in these processes. In this way we hope to generate a much more detailed understanding of the way that cells deal with DNA damage and choose suicide when the damage is too severe.