Roles of LIM domain proteins TRIP6 and LPP at telomeres.

描述（由申请人提供）：端粒对染色体稳定性至关重要。它们确保有效地保护染色体末端，并通过一种专用的酶--端粒酶逆转录酶进行复制。端粒由TTAGGG序列的重复序列组成，并以150 -300个核苷酸长的TTAGGG单链突出端结束。六种蛋白复合物shelterin特异性结合端粒，调节其长度和复制，并确保其保护。未受保护的端粒可以引发DNA损伤反应，导致细胞衰老或凋亡。shelterin复合物能够通过阻止ATM和ATR在端粒的激活来抑制这种反应。该建议的中心假设是，LIM结构域蛋白TRIP 6和LPP，这已经被我们的小组牵连在端粒的DNA损伤反应的抑制，特别是与shelterin相互作用，并参与ATM或ATR的抑制。拟议的实验旨在了解TRIP 6，LPP和shelterin之间的分子相互作用，它们如何以及何时被招募到端粒，以及参与抑制端粒DNA损伤反应的机制和途径。这项工作将揭示抑制人类细胞衰老或凋亡的重要方面，这两者都是有效的肿瘤抑制机制。拟议的研究将确定端粒未探索活动的作用，并指出可能的新靶点，以抑制细胞水平转化状态的发生或维持。

DESCRIPTION (provided by applicant): Telomeres are essential for chromosome stability. They ensure effective protection of chromosome ends, and are replicated by a dedicated enzyme, the telomerase reverse transcriptase. Telomeres consist of repeats of the TTAGGG sequence and end with a150-300 nucleotides-long TTAGGG single stranded overhang. The six protein complex shelterin specifically binds to telomeres, regulates their length and replication, and ensures their protection. The unprotected telomere can elicit a DNA damage response leading to cellular senescence or apoptosis. The shelterin complex is able to repress such a response by preventing the activation of ATM and ATR at telomeres. The central hypothesis of this proposal is that the LIM domain proteins TRIP6 and LPP, which have been implicated by our group in the repression of the DNA damage response at telomeres, specifically interact with shelterin and participate in the repression of ATM or ATR. The proposed experiments seek to understand the molecular interactions between TRIP6, LPP and shelterin, how and when they are recruited to telomeres, and the mechanisms and pathways involved in repressing the DNA damage response at telomeres. This work will uncover important aspects of the suppression of senescence or apoptosis in human cells, which are both potent tumor suppressor mechanisms. The proposed research will establish the role of unexplored activities at telomeres and point to possible new targets to inhibit the onset or maintenance of the transformed state at the cellular level.