The interplay of telomere chromatin dynamics and senescence.

摘要

Chromatin structure exerts immense control over many DNA processes including replication, transcription and DNA repair. The maintenance of telomeric DNA is no exception, yet the interplay between the two is only recently beginning to be understood. Telomeres are organized into nucleoprotein complexes that adopt higher orders structures to form heterochromatin. Emerging evidence suggests that factors involved in assembly of the final structure can contribute to capping and chromatin function to differing degrees, e.g. TRF2, while other functions are much more entangled. In yeast, formation of a silent chromatin structure, spatial segregation of telomeres to the nuclear periphery and telomere length control are regulated by the SIR factors. The multitude of cross-talking proteins and pathways that maintain telomere function and higher order organization have not yet been elucidated and thus it remains unclear how the dynamic regulation of telomeres is achieved through modulation of chromatin. The goal of this thesis was to identify chromatin factors in yeast that limit telomere-dependent lifespan thereby driving senescence. I have for the first time identified such factors whose deletion delay the onset of senescence by changing telomere maintenance and describe their contribution during senescence. These studies contribute to the growing body of literature supporting an important function of telomere maintenance during senescence and organismal ageing and further identify novel interactions that can improve maintenance and prolong lifespan.