Graduation Date

Summer 8-13-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Aimin Peng

Second Advisor

Gregory G. Oakley, Jixin, Dong, and Thomas M. Petro

Abstract

Upon DNA damage,cells promptly activate the cellular DNA damage response (DDR), a surveillance mechanism that leads to DNA repair, cell cycle arrest, and apoptosis. DDR deficiencies cause genomic instability, and are tightly associated with cancer predisposition, immunodeficiency, neurological diseases, and aging. On the other hand, radiation and many chemotherapeutics eliminate cancer cells by inducing DNA damage. Therefore, understanding the DDR and its involvement in cancer is a crucial step toward improving anti-cancer therapeutics. The overarching goal of this project is to delineate how cells respond to, and repair, DNA damage, thus to develop new strategies to overcome cancer resistance.Microtubule associated serine/ threonine kinase like (MASTL),also known as greatwall (GWL), was recently characterized as novel kinase that plays an important role in regulating mitosis. High-level of MASTL expression is frequently observed in various cancers, promoting cancer metastasis and resistance to therapeutics. However, little is known about how MASTL itself is regulated during replication stress and DNA damage, and whether MASTL is involved in immune response, requiring further research to answer these questions. In the beginning of this project, we identified an E3 ubiquitin ligase that mediates MASTL protein degradation. Interestingly, we also highlighted that human cancer cells depleted of this enzyme exhibited weakened DNA damage checkpoints and faster cell recovery from DNA damage. Afterwards, we examined the new function of MASTL in regulating innate immune response. This finding provides conceptual advances of MASTL in promoting tumorigenesis and evasion. Lastly, we characterized a novel function of Sm core proteins in DNA repair. Our research revealed that Sm proteins were associated with DNA damage and were required for homologous recombination (HR), an important mechanism to repair double strand breaks (DSBs). Taken together, our studies delineated several novel mechanisms involved in the DNA damage response and repair, bringing better understandings of how cancer cells bypass DNA damage during tumorigenesis and treatment.Future investigations will potentially lead to new therapeutic strategies that predict cancer resistance and enhance treatment outcomes.

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