Functions of a novel conserved DNA damage response protein family in telomere stability

染色体的游离DNA末端被称为端粒，通常类似于断裂的DNA。因为断裂的DNA是癌症发病的主要因素，细胞试图修复断裂的末端。然而，在端粒的情况下，这种修复过程必须被阻止，因为否则不同的染色体将相互融合。融合的染色体非常脆弱，不能在分裂的细胞之间均匀分布，因此是癌症发展的另一个重要触发因素。因此，染色体末端被一顶帽子覆盖，这就隐藏了它们，使其不受DNA损伤反应机制的影响。从这些考虑可以清楚地看出，在细胞DNA损伤反应和染色体末端之间有密切的联系。此外，最近发现，DNA损伤蛋白也是阻止正常细胞生长所必需的，这一过程被称为衰老。衰老是染色体末端缩短的结果，在癌细胞中不会发生。总而言之，很明显，DNA断裂和衰老是我们理解癌症发展的两个主要问题。我们已经确定了一个新的保守蛋白家族，它参与了酵母和人类对DNA损伤的反应。此外，酵母Mdt1蛋白是端粒帽变化的一个非常敏感的指标。缺乏组织帽子的蛋白质会导致MDT1蛋白中增加几个磷酸基团。我们认为，磷酸偶联的mdt1阻止染色体末端相互融合，或在广泛损伤后与断裂的DNA末端融合。因此，有轻微帽子缺陷的细胞在缺乏MDT1的情况下，因DNA损伤而死亡的速度会增加1000倍。作为这项应用的一部分，我们想要找出MDT1稳定染色体末端的精确机制，并测试我们的假设，即相应的人类蛋白质ASCIZ在保护染色体末端方面也具有类似的功能。

The free DNA ends of chromosomes, termed telomeres, generally resemble broken DNA. Because broken DNA is a major contributing factor to the onset of cancer, cells try to fix broken ends. However, in case of telomeres, such repair processes have to be prevented because otherwise different chromosomes would fuse with each other. Fused chromosomes are very fragile and cannot be evenly distributed between dividing cells, and are therefore another important trigger of cancer development. Therefore, chromosome ends are covered by a cap, which hides them from the DNA damage response machinery. From these considerations it is clear that there are close connections between the cellular DNA damage response and chromosome ends. Moreover, recently it has become clear that DNA damage proteins are also required to stop normal cells from growing, a process termed senescence. Senescence is a consequence of shortened chromosome ends, and does not occur in cancer cells. Altogether, it is clear that DNA breaks and senescence are two of the major questions for our understanding of cancer development. We have identified a novel conserved protein family that is involved in the response to DNA damage in yeast and humans. In addition, the yeast Mdt1 protein is a very sensitive indicator of changes in the telomere cap. Absence of proteins that organise the cap leads to the addition of several phosphate groups to the Mdt1 protein. We propose that phosphate-coupled Mdt1 prevents chromosome ends from fusion with each other, or from fusing with broken DNA ends after widespread damage. As a consequence, cells that have mild cap defects die at an >1000-fold increased rate in response to DNA damage when they also lack Mdt1. As part of this application we want to find out the precise mechanism by which Mdt1 stabilises chromosome ends, and test our hypothesis that the corresponding human protein termed ASCIZ also has similar functions in protecting chromosome ends.