Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

F. Bradley Johnson

Abstract

Cellular senescence is accompanied by dramatic changes in chromatin structure and gene expression. Using S. cerevisiae mutants lacking telomerase (tlc1Δ) to model senescence, we find that with critical telomere shortening the telomere binding protein Rap1 relocalizes to the upstream promoter regions of hundreds of new target genes. The set of new Rap1 targets at senescence (NRTS) are preferentially activated at senescence, and experimental manipulations of Rap1 levels indicate that it contributes directly to NRTS activation, potentially in conjunction with enzymes involved in H2B ubiquitylation (Bre1/Lge1). A notable subset of NRTS includes the core histone-encoding genes; we find that Rap1 contributes to their repression and that histone protein levels decline at senescence. Rap1 and histones also display a target site-specific antagonism that leads to diminished nucleosome occupancy at the promoters of upregulated NRTS. This antagonism apparently impacts the rate of senescence because under-expression of Rap1 or over-expression of the core histones delays senescence. Rap1 relocalization is not a simple consequence of lost telomere binding sites, but rather depends on the Mec1 checkpoint kinase. Rap1 relocalization is thus a novel mechanism connecting DNA damage responses (DDRs) at telomeres to global changes in chromatin and gene expression while driving the pace of senescence.

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