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Regulation of DNA damage tolerance in mammalian cells by post-translational modifications of PCNA

Rie Kanao1, Chikahide Masutani1

  • 1Department of Genome Dynamics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

Mutation Research
|July 2, 2017
PubMed

Insights

Post-translational modifications of proliferating cell nuclear antigen (PCNA) regulate DNA damage tolerance pathways like translesion DNA synthesis (TLS) and template switching. These modifications are crucial for genomic stability but can also cause mutations.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • DNA damage tolerance pathways prevent replication arrest and maintain genomic stability.
  • These pathways, including translesion DNA synthesis (TLS) and template switching, can introduce mutations or rearrangements.
  • Post-translational modifications of proliferating cell nuclear antigen (PCNA) are key regulators of these pathways.

Purpose of the Study:

  • To elucidate the roles of PCNA post-translational modifications in DNA damage tolerance.
  • To understand how these modifications control mutagenic and non-mutagenic repair pathways.
  • To highlight the intricate regulatory mechanisms governing genomic stability.

Main Methods:

  • Focuses on the molecular mechanisms of PCNA ubiquitination (mono- and poly-ubiquitination) and its impact on DNA polymerases.
  • Examines the roles of specific E2-E3 complexes (e.g., RAD6-RAD18, MMS2-UBC13) in PCNA modification.
  • Considers other modifications like SUMOylation, ISGylation, acetylation, methylation, and phosphorylation.

Main Results:

  • PCNA mono-ubiquitination at Lys164 by RAD6-RAD18 facilitates TLS.
  • PCNA K63-linked poly-ubiquitination by RAD6-RAD18 and MMS2-UBC13-HTLF/SHPRH promotes template switching.
  • Simultaneous mono-ubiquitinations on the PCNA ring suggest an uncharacterized damage tolerance mechanism.
  • SUMOylation of PCNA negatively regulates recombination in mammalian cells.

Conclusions:

  • PCNA post-translational modifications are critical for balancing DNA damage tolerance and preventing mutagenesis.
  • Fine-tuning of TLS and template switching via PCNA modifications is essential for genomic integrity.
  • Further research is needed to fully characterize novel PCNA-mediated damage tolerance pathways.
Keywords:
DNA damage tolerancePCNAPost-translational modificationTranslesion synthesisUbiquitination

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