Mechanisms of DNA damage tolerance: post-translational regulation of PCNA

Wendy Leung, Ryan M. Baxley, George Lucian Moldovan, Anja Katrin Bielinsky

Research output: Contribution to journalReview articlepeer-review

52 Scopus citations


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.

Original languageEnglish (US)
Article number10
Issue number1
StatePublished - Jan 1 2019

Bibliographical note

Funding Information:
Research in the Bielinsky laboratory is supported by NIH grant GM074917 to Anja-Katrin Bielinsky and T32 CA009138 to Wendy Leung. We would like to thank Colette B. Rogers for helpful discussion.

Publisher Copyright:
© 2018 by the authors. Licensee MDPI, Basel, Switzerland.


  • DNA damage tolerance
  • PCNA
  • Replication stress
  • Template switching
  • Translesion synthesis
  • Ubiquitination


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