Title
Effective mismatch repair depends on timely control of PCNA retention on DNA by the Elg1 complex
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology
Publication Date
2019-07-26
Document Type
Article
Disciplines
Biochemistry | Genetic Phenomena | Genetics and Genomics | Investigative Techniques | Nucleic Acids, Nucleotides, and Nucleosides
Abstract
Proliferating cell nuclear antigen (PCNA) is a sliding clamp that acts as a central co-ordinator for mismatch repair (MMR) 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. Here we show that timely removal of PCNA from DNA by the Elg1 complex is important to prevent mutations. Although premature unloading of PCNA generally increases mutation rate, the mutator phenotype of elg1Delta is attenuated by PCNA mutants PCNA-R14E and PCNA-D150E that spontaneously fall off DNA. In contrast, the elg1Delta mutator phenotype is exacerbated by PCNA mutants that accumulate on DNA due to enhanced electrostatic PCNA-DNA interactions. Epistasis analysis suggests that PCNA over-accumulation on DNA interferes with both MMR and MMR-independent process(es). In elg1Delta, over-retained PCNA hyper-recruits the Msh2-Msh6 mismatch recognition complex through its PCNA-interacting peptide motif, causing accumulation of MMR intermediates. Our results suggest that PCNA retention controlled by the Elg1 complex is critical for efficient MMR: PCNA needs to be on DNA long enough to enable MMR, but if it is retained too long it interferes with downstream repair steps.
Keywords
Genome integrity, repair and replication
Rights and Permissions
Copyright The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI of Published Version
10.1093/nar/gkz441
Source
Nucleic Acids Res. 2019 Jul 26;47(13):6826-6841. doi: 10.1093/nar/gkz441. Link to article on publisher's site
Journal/Book/Conference Title
Nucleic acids research
Related Resources
PubMed ID
31114918
Repository Citation
Paul Solomon Devakumar LJ, Gaubitz C, Lundblad V, Kelch BA, Kubota T. (2019). Effective mismatch repair depends on timely control of PCNA retention on DNA by the Elg1 complex. Open Access Articles. https://doi.org/10.1093/nar/gkz441. Retrieved from https://escholarship.umassmed.edu/oapubs/3931
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Biochemistry Commons, Genetic Phenomena Commons, Genetics and Genomics Commons, Investigative Techniques Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons