Roles of LIM domain proteins TRIP6 and LPP at telomeres.

描述（申请人提供）：端粒对染色体的稳定性至关重要。它们确保对染色体末端的有效保护，并由一种专门的酶——端粒酶逆转录酶进行复制。端粒由TTAGGG序列的重复组成，末端有150-300个核苷酸长的TTAGGG单链悬垂。六种蛋白质复合物庇护蛋白特异性地与端粒结合，调节端粒的长度和复制，并确保端粒受到保护。未受保护的端粒可引起DNA损伤反应，导致细胞衰老或凋亡。庇护蛋白复合物能够通过阻止端粒上ATM和ATR的激活来抑制这种反应。本研究的核心假设是，LIM结构域蛋白TRIP6和LPP与端粒DNA损伤反应的抑制有关，它们与庇护蛋白相互作用，参与抑制ATM或ATR。本实验旨在了解TRIP6、LPP和庇护蛋白之间的分子相互作用，它们如何以及何时被招募到端粒，以及抑制端粒DNA损伤反应的机制和途径。这项工作将揭示人类细胞衰老或凋亡抑制的重要方面，这两者都是有效的肿瘤抑制机制。拟议的研究将确定端粒中未被探索的活动的作用，并指出可能的新目标，以抑制细胞水平上转化状态的开始或维持。

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.