The Role of Shelterin-Mediated Telomere Remodeling in Chromosome End Protection

University Of California-Berkeley, Berkeley CA

Investigators

Abstract

The goal of this project is to elucidate the mechanism of protection and maintenance of telomeres at the ends of human chromosomes. The ends of eukaryotic chromosomes need to be protected against inappropriate DNA damage repair reactions (DDR), DNA degradation and incomplete DNA replication in order to maintain genomic stability and proper functioning. The solution to these challenges is to form a protective telomere cap structure that consists of specialized repeat DNA sequences and associated factors that together form the shelterin complex. Gradual shortening of telomeres in dividing cells triggers DDR and cell cycle arrest. Thus telomeres are referred to as internal biological clocks that determine the proliferative lifespan of an organism and function as major anticancer barriers. Detailed knowledge of how telomeres form a protective cap at the chromosome end and how progressive telomere shortening leads to replicative senescence is needed to better understand aging and cancer. This project will also help to establish educational outreach programs for high school students from underprivileged areas of Oakland, CA. To attract high school and undergraduate students to scientific research, summer research opportunities, seminars and science fairs will be organized in local public schools. The results of the research will be integrated into a new curriculum that will be developed for Physics undergraduates wishing to pursue a graduate career in the life sciences. How shelterin prevents the DDR machinery from gaining access to chromosome ends, particularly the single-stranded telomeric overhang, remains unclear. Recently, it has been suggested that shelterin remodels telomeric chromatin into a highly compact structure that reduces the accessibility of DDR proteins to telomere ends. Using super-resolution imaging in vivo, the project aims to reveal the role of shelterin in safeguarding the telomeric overhang within telomeric chromatin. The changes in organization of telomeric chromatin will be determined as telomeres shorten in dividing cells to understand the mechanism that triggers DDR accumulation at chromosome ends before senescence. Additionally, to determine whether compaction of telomeric tracts is required and sufficient to antagonize binding of DDR proteins to telomeric overhangs, the structure of shelterin-bound telomeric DNA will be solved using cryoelectron tomography and its structure-function properties will be investigated by single molecule experiments in vitro.