FHA domain-dependent functions of cell cycle checkpoint kinases

人类染色体作为遗传信息的载体，经常受到DNA损伤。这通常是自发发生的，仅仅是细胞能量消耗的副产物DNA残基氧化的结果，或者是细胞生长过程中染色体复制过程中的错误的结果，并由化学或物理因素加剧，例如致癌物、紫外线或x射线。DNA损伤如果没有得到适当的修复，可能会产生严重的后果，导致大量DNA丢失或不适当的基因组重排，从而导致基因组不稳定，最终可能导致癌症。为了防止这种可怕的后果，从酵母到人类的所有生物都含有分子检查点，这些检查点可以感知DNA损伤的存在，然后激活细胞反应程序，包括损伤修复和防止损伤持续存在时的细胞分裂。这些分子检查点在整个进化过程中是高度保守的，这使我们能够分析酵母菌等简单生物体的细节，从而得出它们在更复杂的人类细胞中的功能的一般结论。沿着这些思路，我们正在研究与人类Chk2蛋白相似的两种酵母蛋白的功能，Chk2蛋白是一种肿瘤抑制因子，在患有Li-Fraumeni多癌综合征的家族中发生突变。我们已经确定了这些蛋白质在DNA损伤剂治疗后促进细胞存活的新途径，并将在本提案中进一步描述这些途径。

Human chromosomes as carriers of the genetic information are constantly subjected to DNA damage. This usually occurs spontaneously, simply as a result of oxidation of DNA residues as a byproduct of cellular energy consumption or as a result of errors during chromosome duplication in growing cells, and is compounded by chemical or physical agents, for example carcinogens, UV rays or X-rays. DNA damage can have severe consequences if not properly repaired, leading to genomic instability with loss of vast tracts of DNA or inappropriate genome rearrangements, that may ultimately give rise to cancer. To prevent such dire consequences, all organisms from yeast to man contain molecular checkpoints that sense the presence of DNA damage and then activate a cellular response program that includes damage repair and prevention of cell division while damage persists. These molecular checkpoints are highly conserved throughout evolution which allows us to analyse the details involved in simple organisms such as yeast, to draw general conclusions on their function in more complex human cells. Along these lines, we are studying the function of two yeast proteins that are similar to the human Chk2 protein, a tumour suppressor that is mutated in a subset of families suffering from the Li-Fraumeni multi-cancer syndrome. We have identified new pathways by which these proteins contribute to the survival of cells after treatment with DNA damaging agents and will further charaterise these in the present proposal.