Regulation of heat shock factor 1 in DNA damage induced senescence

Thesis (Ph.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Aging is the single most important risk factor in the development of a variety of diseases, such as neurodegenerative diseases, cardiovascular diseases and cancer. Many causes of the age-related diseases are due to decreased protein homeostasis (proteostasis). To maintain proteostasis, cells have developed stress responses, such as heat shock response (HSR). HSR is attenuated with aging, and its activation leads to relief of several age-associated diseases. Because of this apparent relationship between attenuation of HSR and age-related diseases, we suggested that decreased heat shock factor 1, Hsf1, function contributes to cellular senescence and aging. Hence, suppression of HSR in aging cells may be responsible for the collapse in protein homeostasis and not only lead to pathology but also can shorten lifespan of the organism. Here we investigated the connection between suppression of HSR and the development of cellular senescence. We demonstrated that HSR is suppressed in fibroblasts from the segmental progerioid Werner Syndrome patients, which undergo premature senescence. Similar suppression of HSR was seen in normal fibroblasts which developed senescence in response to DNA damaging treatments. Specifically, p53 and p38MAPK pathways contributed to the HSR suppression. The HSR suppression resulted from the decrease in the translation regulator HuR, which led to downregulation of SIRT1, culminating in inhibition of both activity and transcription of Hsf1. Importantly, we discovered that Hsf1 suppression signals back to further activate the p38MAPK pathway, which in turn stimulates senescence. Therefore, downregulation of Hsf1 by DNA damage plays an important role in development and maintenance of DNA damage-induced cell senescence