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

染色体的游离DNA末端称为端粒，通常类似于断裂的DNA。因为断裂的DNA是导致癌症发生的主要因素，细胞试图修复断裂的末端。然而，对于端粒来说，这种修复过程必须被阻止，否则不同的染色体就会相互融合。融合染色体非常脆弱，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，染色体末端被一层帽所覆盖，从而使它们不受DNA损伤反应机制的影响。从这些考虑可以清楚地看出，细胞DNA损伤反应与染色体末端之间存在着密切的联系。此外，最近已经很清楚，DNA损伤蛋白也需要阻止正常细胞生长，这一过程被称为衰老。衰老是染色体末端缩短的结果，不会发生在癌细胞中。总之，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。缺乏组织帽的蛋白质会导致Mdt1蛋白上添加几个磷酸基团。我们提出，磷酸偶联Mdt1阻止染色体末端相互融合，或在广泛损伤后阻止与断裂的DNA末端融合。因此，当缺乏Mdt1时，具有轻度帽缺陷的细胞在DNA损伤时的死亡率增加了1000倍。作为这项应用的一部分，我们想要找出Mdt1稳定染色体末端的确切机制，并验证我们的假设，即相应的人类蛋白质ASCIZ也具有保护染色体末端的类似功能。

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.