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Investigation into the molecular mechanisms underlying circadian rhythm disruption and human cancer

Doctor of Philosophy / Humans and all mammals have an internal timekeeping mechanism named the circadian clock that enables anticipation and response to the approximately 24-hour solar day and other environmental conditions. The circadian clock is self-sustained and coordinates rhythmic physiological functions such as the sleep/wake cycle, body temperature, hormone production, and metabolism, together forming the organism's "circadian rhythm." Chronic disruption of the circadian rhythm is known to be carcinogenic , but the molecular explanation for this phenomenon remains elusive. The purpose of my dissertation work was to investigate the role of mutations commonly associated with cancer as a potential molecular mechanism of circadian clock dysfunction.

The PER2 gene produces the PER2 protein, which our laboratory has previously shown to interact with p53, a key "tumor suppressor" that responds to DNA damage. When not functional, these tumor suppressors can lead to uncontrolled cell division and eventually cancer. We focused on a mutation in p53 that changes p53's function and its interaction with PER2 in a manner that also prevents PER2 from functioning normally within the circadian clock. This dual dysregulation leads to the loss of rhythmic clock gene expression, and in turn, changes to cellular fitness, metabolism, and proliferation.

Identiferoai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/116087
Date22 August 2023
CreatorsJanoski, Jesse Ryan
ContributorsBiological Sciences, Finkielstein, Carla V., Smyth, James, Lemkul, Justin Alan, Kojima, Shihoko, Pan, Yuchin Albert
PublisherVirginia Tech
Source SetsVirginia Tech Theses and Dissertation
LanguageEnglish
Detected LanguageEnglish
TypeDissertation
FormatETD, application/pdf, application/pdf
RightsCreative Commons Attribution-NonCommercial 4.0 International, http://creativecommons.org/licenses/by-nc/4.0/

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