Author ORCID Identifier

https://orcid.org/0000-0002-4604-9681

Semester

Summer

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Biology

Committee Chair

Jennifer E. Gallagher

Committee Member

Jennifer Hawkins

Committee Member

Antony Jose

Committee Member

Stephen DiFazio

Committee Member

Aaron Robart

Abstract

Telomerase is an enzyme found in rapidly dividing cells that maintains chromosome ends and prevents the loss of genetic information during cell division. When telomerase is inactive, cells gradually lose their telomeres and eventually stop dividing. In yeast, a rare subset of cells can bypass this growth arrest by switching to a recombination-based mechanism to maintain telomeres. Therefore, yeast provides a powerful system to study this adaptation, as telomerase-deficient strains can generate 'survivors' that mimic the Alternative Lengthening of Telomeres (ALT) pathway observed in some human tumors. In this work, my goal was to examine how a telomerase-null (TLC1-deletion) strain of yeast adapts over time by tracking physiological, metabolic, and transcriptomic changes across serial passages. To do this, cultures were repeatedly diluted into fresh media, allowing them to undergo multiple generations of growth. Each passage captured a different stage of adaptation—from early crisis to full survivor formation. Early-passage cells showed physical signs of mitochondrial dysfunction, poor respiration, and increased oxidative stress, consistent with a crisis-like state. As survivors emerged, these cells displayed improved growth, restored respiration in a subset of the population, and changes in metabolite profiles, especially in amino acid and antioxidants. Transcriptome analysis revealed that genes involved in mitochondrial activity, DNA recombination, and stress response were strongly upregulated during this transition, while growth-related pathways were repressed. Although each culture followed a slightly different path through in-lab evolution, one theme remained consistent: mitochondria were central to the adaptation process. Together, these findings suggest that surviving telomerase loss is not just about maintaining telomeres, it also requires broad metabolic rewiring and stress management to support long-term proliferation.

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