Dissertations, Theses, and Capstone Projects

Date of Degree

9-2024

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Alicia Melendez

Committee Members

Cathy Savage-Dunn

Jill Bargonetti

Judith L. Yanowitz

Iva S. Greenwald

Subject Categories

Biology | Cell Biology | Developmental Biology | Genetics

Keywords

Autophagy, Meiosis, C. elegans, Aging

Abstract

Autophagy is an evolutionarily conserved multi-step recycling process in which cellular material is enclosed in the double membrane-bound autophagosome, which fuses with the lysosome to degrade its contents. Autophagy is essential for development and cellular adaptation to environmental or intracellular stress and is an important regulator of germline stem cell homeostasis in the model nematode C. elegans. We sought to determine if autophagy is important for genome stability during meiosis and found that the core adult C. elegans autophagy genes bec-1, atg-7, unc-51, and atg-18 were all required for proper meiotic development of oocytes. Loss of these genes led to lethality, chromosome fusions, poorly condensed chromosomes or univalent chromosomes which can all indicate unrepaired DNA damage. Using CRISPR-Cas9 gene editing we tagged BEC-1 with an auxin inducible degron at the endogenous locus and showed that BEC-1 activity is required in the somatic and germline tissues in adulthood to regulate meiosis. We also found that bec-1 and atg-7 interacted with the p53 homolog cep-1 to regulate DNA repair pathway choice, specifically in promoting high fidelity repair through homologous recombination versus error-prone non-homologous end joining. Autophagy genes such as bec-1 and atg-7, and p53 are commonly mutated in many human diseases, including cancers and neurodegenerative disorders. Further investigation to clarify in which tissue-mediated expression of autophagy genes are interacting with cep-1 could provide insight into how autophagy regulates genome integrity to influence disease processes.

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