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DNA damage tolerance: when it's OK to make mistakes

Nature Chemical Biology volume 5, pages 82–90 (2009)Cite this article

Abstract

Mutations can be beneficial under conditions in which genetic diversity is advantageous, such as somatic hypermutation and antibody generation, but they can also be lethal when they disrupt basic cellular processes or cause uncontrolled proliferation and cancer. Mutations arise from inaccurate processing of lesions generated by endogenous and exogenous DNA damaging agents, and the genome is particularly vulnerable to such damage during S phase. In this phase of the cell cycle, many lesions in the DNA template block replication. Such lesions must be bypassed in order to preserve fork stability and to ensure completion of DNA replication. Lesion bypass is carried out by a set of error-prone and error-free processes collectively referred to as DNA damage tolerance mechanisms. Here, we discuss how two types of DNA damage tolerance, translesion synthesis and template switching, are regulated at stalled replication forks by ubiquitination of PCNA, and the conditions under which they occur.

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Figure 1: Overview of DNA damage tolerance pathways and PCNA ubiquitination.
Figure 2: Translesion synthesis pathway.
Figure 3: Ubiquitin conjugation pathway and enzymes involved in PCNA ubiquitination.
Figure 4: Domain architecture and functions of the E3 ubiquitin ligase Rad5 and its putative orthologs SHPRH and HLTF.
Figure 5: Coordinated activation of PCNA ubiquitination and the ATR-dependent checkpoint response at a stalled replication fork.

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Acknowledgements

The authors thank T. Wandless, A. Hahn, J.-R. Lin and M. Zeman for helpful discussions and critical reading of the manuscript.

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  1. Debbie J. Chang and Karlene A. Cimprich are in the Department of Chemical and Systems Biology, Stanford University School of Medicine, Clark Center, 318 Campus Drive, W350B, Stanford, California 94305-5441, USA.,

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Correspondence to Karlene A Cimprich.

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Chang, D., Cimprich, K. DNA damage tolerance: when it's OK to make mistakes. Nat Chem Biol 5, 82–90 (2009). https://doi.org/10.1038/nchembio.139

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