Graduation Date

Summer 8-14-2026

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Genetics, Cell Biology & Anatomy

First Advisor

Gargi Ghosal, PhD

Abstract

DNA-protein crosslinks (DPCs) are covalent crosslinks of protein to the DNA that are generated by endogenous and exogenous DNA-damaging agents. DPCs are toxic lesions that obstruct DNA replication and transcription processes. Unrepaired DPCs result in DNA breaks leading to genome instability, genetic diseases, and cancer. DPCs are resolved through two main mechanisms: Replication- and Transcription-coupled DPC repair pathways. Previous studies showed that SPRTN, a replication-coupled DNA-dependent metalloprotease, cleaves DPCs, generating DNA-peptide crosslinks and DNA breaks which are subsequently repaired by downstream homologous recombination (HR) or non-homologous end-joining (NHEJ) DNA repair pathways. Mutations in key DPC repair proteins like TDP1/2, SPRTN, RAD50, MRE11, NBS1 lead to genome instability, progeria, and genetic diseases characterized by neuropathy, immunodeficiency, microcephaly, and cancer predisposition. Importantly, DPC-inducing agents are used for cancer therapy. Cancer cells with efficient DPC repair pathways will repair damage induced by chemotherapeutic agents and become resistant. Thus, delineating the molecular mechanism and identifying regulators of the DPC repair pathway is imperative. The precise molecular mechanism and regulators of the DPC repair pathway are largely unknown. Our study identifies DHX40, a putative DEAH-box RNA helicase, as a novel regulator of the DPC repair pathway. We show that DHX40 sensitizes mismatch repair proficient cells to  TOP1 and DNMT1 DPC-inducing agents.

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