Genetics of telomerase in C. elegans

描述(申请人提供)：该项目的长期目标是发展秀丽线虫作为研究端粒酶和端粒生物学的模型系统。端粒酶通过在染色体末端添加从头端粒重复序列来维持染色体的完整性。大多数人类体细胞缺乏端粒酶，并在增殖时表现出端粒侵蚀，这可能导致关键的端粒缩短和衰老。我们建议研究一种混杂的DNA复制过程，该过程可能促进严重缩短的端粒上的大规模亚端粒基因组复制。这一过程可能在基因组进化中广泛相关，并可能有助于肿瘤的发生。我们假设端粒功能障碍可以激活一个或多个应激反应通路：1)可能触发对机体生理的全身性影响，从而导致衰老或与年龄相关的疾病；2)在没有端粒酶的情况下，端粒复制可能通过称为端粒替代延长(ALT)的端粒复制途径促进生存。染色体生物学领域的一个长期假设是，基因组进化的各个方面可能是对压力的精心安排的反应。拟议的研究将在端粒生物学的背景下使用后生动物模型系统来解决这一假说，在该模型系统中，各种保守的应激反应途径已经被很好地描述，并且可以使用强大的遗传、细胞生物学和基因组工具：线虫。

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop C. elegans as a model system for studying telomerase and telomere biology. Telomerase maintains chromosome integrity by adding de novo telomere repeats to chromosome termini. Most human somatic cells lack telomerase and display telomere erosion as they proliferate, which can lead to critical telomere shortening and senescence. We propose to study a promiscuous DNA replication process that may promote large-scale subtelomeric genome duplications at critically shortened telomeres. This process may be broadly relevant in genome evolution and could contribute to tumorigenesis. We hypothesize that telomere dysfunction can activate one or more stress response pathways that 1) may trigger systemic effects on organismal physiology that could contribute to aging or age-related diseases, 2) may promote survival in the absence of telomerase via a telomerase-independent telomere replication pathway termed Alternative Lengthening of Telomeres (ALT). A long-standing hypothesis in the field of chromosome biology is that aspects of genome evolution could be an orchestrated response to stress. The proposed studies will address this hypothesis in the context of telomere biology using a metazoan model system where a variety of conserved stress response pathways have been well characterized and where powerful genetic, cell biology and genomic tools are available: the nematode C. elegans.