Date of Award

8-2024

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Biosciences

First Advisor

Shailja Pathania

Second Advisor

Jill Macoska

Third Advisor

Changmeng Cai, Alexey Veraksa, Jason Evans, Zoltan Szallasi

Abstract

BRCA2 is a tumor suppressor gene. Germline mutation in BRCA2 significantly elevates the risk of breast, ovarian, pancreatic and prostate cancer. In this project, I focused on investigating molecular mechanisms that drive tumorigenesis and chemoresistance in BRCA2 mutation carriers and developing novel preventative and therapeutic strategies to reduce the cancer burden in individuals carrying BRCA2 mutation. A critical mechanism through which BRCA2 maintains genomic stability, and therefore preventing the formation of these cancers, is the suppression of replication stress (RS) through facilitating stalled replication fork repair. I have identified a novel role of BRCA2 in stalled fork repair, and show that BRCA2 inhibits the accumulation of a toxic intermediate at stalled forks, the ubiquitinated, phosphorylated RPA (ubq-pRPA)-coated single-stranded DNA (ssDNA). I found that such ssDNA persistently accumulated in BRCA2-deficient cells under RS resulting in two consequences: 1) the ssDNA becomes a target for cytosine deamination, leading to the increased uracil-in-DNA (U-DNA) accumulation. Removing uracil on ssDNA by UNG2 followed by downstream process significantly contributes to the genomic instability in BRCA2-deficient cells. 2) persistent accumulation of ssDNA leads to the exhaustion of replication protein A (RPA), inducing nucleotide excision repair (NER) deficiency. Last, I investigated early pathogenic events that drive the transition of ostensibly normal cells (BRCA2+/-) to tumor cells.

Comments

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