The regulation of translesion synthesis through the binding and activation of polymerases by PCNA
Year: 2016
Type: dissertation
Abstract: DNA damage causes replication forks to stall, which can ultimately lead to double strand breaks, chromosomal rearrangements, and cell death. Proliferating cell nuclear antigen is a clamp protein which encircles DNA and acts as a sliding platform for proteins that will act on the DNA, including polymerases. Replication fork stalling causes PCNA to be mono-ubiquitylated, resulting in a polymerase switch from the classical polymerases that perform replication to the Y-family polymerases which conduct translesion synthesis (TLS) to bypass the DNA damage and allow replication to continue. Y-family polymerases include DNA polymerases eta, kappa, iota, and Rev1. The mechanism by which these polymerases are assembled into multi-protein complexes which include PCNA has previously not been well-understood. The studies outlined below demonstrate that ternary complexes involving PCNA, Rev1, and pol η can adopt multiple conformations which can rapidly interconvert. Additionally, I have demonstrated that ubiquitin stimulates the catalytic activity of DNA polymerase eta through a novel interaction with the catalytic core. These studies represent significant progress towards understand the regulation of TLS polymerase activity through both recruitment to and activation by ubiquitylated PCNA.
Authors: Elizabeth Marie Boehm, M. Todd Washington, Jon Houtman, Maria Spies, Kris DeMali, Ernesto Fuentes, Madeline Shea
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2759085935