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Title: Effective mismatch repair depends on timely control of PCNA retention on DNA by the Elg1 complex
Author: Paul Solomon Devakumar, Lovely Jael
ISNI:       0000 0004 7658 8920
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2018
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Proliferating cell nuclear antigen (PCNA) is a sliding clamp that acts as a central co-ordinator for mismatch repair as well as DNA replication. Loss of Elg1, the major subunit of the PCNA unloader complex, causes over-accumulation of PCNA on DNA and also increases mutation rate, but it has been unclear if the two effects are linked. In this study, I showed that timely control of PCNA retention on DNA by Elg1 replication factor C-like complex (Elg1-RLC) ensures correct mismatch repair. Although premature unloading of PCNA generally increases mutation rate, PCNA mutants PCNA-R14E and PCNA-D150E that spontaneously fall off DNA attenuate the mutator phenotype of elg1Δ. In contrast, PCNA-D21K that accumulates on DNA due to enhanced electrostatic PCNA-DNA interactions exacerbates the elg1Δ mutator phenotype. Next, I addressed how accumulation of PCNA on DNA increases mutation rate. Epistasis analysis suggests that PCNA over-accumulation on DNA predominantly prevents the Msh2-Msh6-dependent and Exo1-independent mismatch repair pathways. In elg1Δ, over-retained PCNA hyper-recruits the Msh2-Msh6 mismatch recognition complex through its PCNA-interacting peptide motif, causing accumulation of mismatch repair intermediates. The results suggest that PCNA retention controlled by the Elg1-RLC is critical for efficient mismatch repair: PCNA needs to be on DNA long enough to enable mismatch repair, but if it is retained too long it interferes with downstream repair steps.
Supervisor: Kubota, Takashi ; Donaldson, Anne D. Sponsor: University of Aberdeen
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: DNA repair ; Proliferating cell nuclear antigen