The Mechanism of Telomere Recombination in Yeast

描述（由申请人提供）：生物学的核心问题之一是端粒如何参与遗传稳定性的问题。重组端粒延长（RTE）是细胞在端粒酶活性缺失的情况下延长端粒的一种机制。当端粒酶缺失时，人类ALT（端粒选择性延长）肿瘤依靠RTE延长端粒并继续细胞分裂，这在大多数人类体细胞中都是如此。Mre11是参与端粒维持和体内平衡的组分之一，是一种多功能蛋白，其主要作用是识别和修复双链断裂。拟议研究的长期目标是确定细胞经历重组端粒延伸（RTE）的机制，并将这一知识应用于由ALT细胞引起的人类癌症（如骨肉瘤）的治疗。该项目的具体目标是更清楚地描述具体的重组

DESCRIPTION (provided by applicant): One of the central issues in biology is the question of how telomeres are involved in genetic stability. Recombinational telomere elongation (RTE) is a mechanism by which cells elongate their telomeres in the absence of telomerase activity. Human ALT (alternative lengthening of telomeres) tumors depend upon RTE to lengthen telomeres and continue cellular division when telomerase is absent, as is the case in most human somatic cells. One of the components involved in telomere maintenance and homeostasis is Mre11, a multifunctional protein whose primary role is the recognition and repair of double-strand breaks. The long-term goal of the proposed research is to determine the mechanism by which cells undergo recombinational telomere elongation (RTE) and to apply this knowledge to the treatment of human cancers, such as osteosarcomas, caused by ALT cells. The specific objective of this project is to more clearly characterize the specific recombinational mechanism responsible for telomere elongation in yeast. These experiments use the novel gain-of-function allele, mre11- A470T, which is capable of inducing an unusual variation of telomeric recombination in telomerase-negative cells. This variation is responsible for an observed bypass of senescence in telomerase-negative, mre11-A470T cells. The central hypothesis is that RTE in yeast is accomplished via the break-induced replication (BIR) pathway and that the mre11-A470T allele induces aberrant telomeric BIR events. This alteration of the BIR pathway may occur by a generalized or specific enhancement of the activity, regulation, or specificity of BIR enzymatic machinery. The rationale behind the proposed experiments is that study of mre11-A470T provides an excellent and unique opportunity to probe the regulation of telomere recombination by Mre11. The significance of this work is that it will provide us with a greater understanding of the regulation, requirements, and characteristics of recombinational telomere elongation and the role of Mre11 in this process. This information will be essential to our understanding and treatment of the cancer progression of human ALT cells.