Epigenetic modifications do not involve changes in the DNA sequence and eventhough heritable, but reversible. It has been proposed that the ageing phenotype is, at least in part, due to the progressive divergance from a youthful chromatin modifications to one that contributes to molecular signatures of ageing. The Sirtuin family of NAD+-dependent lysine deacetylases has a long and controversial relation with ageing. My research has focused on the SIRT6, with a particular emphasis on elucidating how SIRT6 contributes to oxidative stress response and epigenetic maintenance pathways. Using a series of molecular, cellular, proteomics experiments, I identify several novel pathways by which SIRT6 contributes to epigenetic maintenance, including recruitment of BAF complex to promoter of anti-oxidant genes, monitoring the chromatin topology, stimulation of DNA DSB repair, rejuvenation of senescent transcriptome to juvenile state, and inhibition of cellular growth under growth factor deprivation through suppression of ribosome biogenesis. Given that DNA repair pathway, metabolism and the stress response are linked with lifespan, the overlapping function of SIRT6 regarding metabolism, epigenome and DNA repair provides evidence that chromatin modifiers can integrate distinct cellualar processes such as metabolic, epigenetic regulation and the DNA damage response to influence longevity.
|Advisor:||Gorbunova, Vera, Seluanov, Andrei|
|Commitee:||Bohmann, Dirk, Fu, Dragony, Bi, Xin, Bulger, Michael|
|School:||University of Rochester|
|Department:||School of Arts and Sciences|
|School Location:||United States -- New York|
|Source:||DAI-B 82/3(E), Dissertation Abstracts International|
|Subjects:||Biology, Cellular biology, Physiology, Aging|
|Keywords:||SIRTG, Epigenetic modifications, Oxidative stress response|
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