Biomedical Sciences ETDs
Mechanistic Study of DNA Ligase IV-Mediated Double-Strand Break Repair in Non-Homologous End Joining
Publication Date
Fall 9-6-2024
Abstract
Non-homologous end joining (NHEJ) is a crucial double-strand break repair pathway in mammalian cells, resolving DNA damage from ionizing radiation and during V(D)J recombination. Although DNA Ligase IV is the only mammalian DNA ligase involved in NHEJ, it functions as a single-turnover enzyme in vitro. Recent cryo-electron microscopy (cryo-EM) studies revealed two LigIV molecules at the NHEJ synapse, supporting the hypothesis that two ligase molecules are needed for DSB repair by NHEJ. This study aims to validate this hypothesis by providing evidence for coordinated ligation at optimal distance and polarity preference for catalytic activity by LigIV. We determined that coordination occurs at a 4nt distance, though LigIV's binding is less stable and prone to exchange. There is promising potential of LigIV inhibitors for radiosensitization, although our pan ligase inhibitor derivatives did not yield radiosensitizing candidates. Further understanding of LigIV's role in NHEJ could advance therapeutic strategies to improve cancer treatments.
Keywords
DNA repair, DNA Ligase IV, NHEJ, double-strand break repair, Ligation
Document Type
Dissertation
Language
English
Degree Name
Biomedical Sciences
Level of Degree
Doctoral
Department Name
Biomedical Sciences Graduate Program
First Committee Member (Chair)
Hua-Ying Fan
Second Committee Member
Alan E. Tomkinson
Third Committee Member
David Lee
Fourth Committee Member
Laurie G. Hudson
Recommended Citation
Naila, Tasmin and Alan E. Tomkinson. "Mechanistic Study of DNA Ligase IV-Mediated Double-Strand Break Repair in Non-Homologous End Joining." (2024). https://digitalrepository.unm.edu/biom_etds/270
