DOI
https://doi.org/10.25772/8GV8-QF95
Defense Date
2020
Document Type
Thesis
Degree Name
Master of Science
Department
Human Genetics
First Advisor
Larisa Litovchick
Abstract
The Dimerization Partner, Rb-like, E2F, And MuvB (DREAM) complex was identified in humans due to homology of the genes involved in the D. melanogaster dREAM complex. It assembles during cellular arrest, or G0, to function as a transcriptional repressor of cell cycle genes. It is known that phosphorylation of LIN52 at serine 28 is necessary for the critical DREAM forming interaction between LIN52 and the pocket protein p130. Our laboratory has previously shown that gene editing of LIN52 to replace serine 28 with alanine (S28A) prevents phosphorylation by the kinase DYRK1A and inhibits DREAM formation. Here we have confirmed this model and used it to investigate cell cycle regulation in the absence of DREAM. Our approach included both in vitro and in vivo methods using genetically engineered S28A Lin52 mice and immortalized MEFs. We have shown that DREAM loss deregulates the cell cycle, increasing proliferation and displaying reduced oncogenic Ras induced senescence. Restoration of DREAM rescues these phenotypes to a degree. While characterizing S28A mice we observed a general decrease in body weight and shortened lifespan in males. Overall, we have demonstrated the role of DREAM in control of cell cycle exit and how loss of this complex leads to rapid proliferation, potentially aiding in cellular transformation.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-1-2020