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Mechanisms of DNA Damage Tolerance: Post-Translational Regulation of PCNA

Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Author to whom correspondence should be addressed.
Genes 2019, 10(1), 10;
Received: 16 November 2018 / Revised: 18 December 2018 / Accepted: 19 December 2018 / Published: 24 December 2018
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
DNA damage is a constant source of stress challenging genomic integrity. To ensure faithful duplication of our genomes, mechanisms have evolved to deal with damage encountered during replication. One such mechanism is referred to as DNA damage tolerance (DDT). DDT allows for replication to continue in the presence of a DNA lesion by promoting damage bypass. Two major DDT pathways exist: error-prone translesion synthesis (TLS) and error-free template switching (TS). TLS recruits low-fidelity DNA polymerases to directly replicate across the damaged template, whereas TS uses the nascent sister chromatid as a template for bypass. Both pathways must be tightly controlled to prevent the accumulation of mutations that can occur from the dysregulation of DDT proteins. A key regulator of error-prone versus error-free DDT is the replication clamp, proliferating cell nuclear antigen (PCNA). Post-translational modifications (PTMs) of PCNA, mainly by ubiquitin and SUMO (small ubiquitin-like modifier), play a critical role in DDT. In this review, we will discuss the different types of PTMs of PCNA and how they regulate DDT in response to replication stress. We will also cover the roles of PCNA PTMs in lagging strand synthesis, meiotic recombination, as well as somatic hypermutation and class switch recombination. View Full-Text
Keywords: PCNA; DNA damage tolerance; translesion synthesis; template switching; ubiquitination; replication stress PCNA; DNA damage tolerance; translesion synthesis; template switching; ubiquitination; replication stress
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Leung, W.; Baxley, R.M.; Moldovan, G.-L.; Bielinsky, A.-K. Mechanisms of DNA Damage Tolerance: Post-Translational Regulation of PCNA. Genes 2019, 10, 10.

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