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  • Review Article
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Suffering in silence: the tolerance of DNA damage

Nature Reviews Molecular Cell Biology volume 6, pages 943–953 (2005)Cite this article

Key Points

  • DNA-damage tolerance involves multiple mechanisms for the bypass of template damage in DNA that arrests high-fidelity DNA replication.

  • DNA-damage tolerance can occur either by direct DNA synthesis across sites of base damage (translesion DNA synthesis (TLS)) or by various mechanisms that obviate the need to replicate directly across the damage.

  • TLS is effected by specialized DNA polymerases. Prokaryotes contain two such enzymes, whereas higher eukaryotes have numerous specialized DNA polymerases.

  • The mechanism of TLS synthesis requires numerous polymerase-switching events. In higher eukaryotes, these switching events are thought to involve interactions with one another, with monoubiquitylated proliferating cell nuclear antigen (PCNA) and possibly with REV1 protein.

  • Several mouse strains have been generated that are defective in various specialized DNA polymerases.

  • Some specialized DNA polymerases are apparently involved in somatic hypermutation in the immune system.

  • DNA-damage tolerance by mechanisms other than TLS are known as post-replication recombinational repair and replication fork regression, the details of which remain to be clearly defined.

Abstract

When cells that are actively replicating DNA encounter sites of base damage or strand breaks, replication might stall or arrest. In this situation, cells rely on DNA-damage-tolerance mechanisms to bypass the damage effectively. One of these mechanisms, known as translesion DNA synthesis, is supported by specialized DNA polymerases that are able to catalyse nucleotide incorporation opposite lesions that cannot be negotiated by high-fidelity replicative polymerases. A second category of tolerance mechanism involves alternative replication strategies that obviate the need to replicate directly across sites of template-strand damage.

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Figure 1: Cellular responses to DNA damage.
Figure 2: Three-dimensional structures of a high-fidelity DNA polymerase and a specialized DNA polymerase.
Figure 3: A model for translesion DNA synthesis in prokaryotes.
Figure 4: A model of translesion DNA synthesis in eukaryotic cells.
Figure 5: Post-replication (gap-filling) repair and replication-fork regression.

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Acknowledgements

I thank S. Squires, P. Fischhaber, L. McDaniel, R. Schultz, N. Kosarek, G. Walker and W. Siede for critical review of the manuscript and helpful discussions. Work in my laboratory is supported by a research grant from the United States Public Health Service (USPHS).

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  1. Department of Pathology, Laboratory of Molecular Pathology, University of Texas Southwestern Medical Center, Dallas, 75390-9072, Texas, USA

    Errol C. Friedberg

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DATABASES

Entrez Gene

MMS2

POLH

Poli

Polk

Poll

Polm

RAD5

UBC13

umuC

umuD

Swiss-Prot

PCNA

PriA

PriC

RAD6

RAD18

RecA

REV1

FURTHER INFORMATION

E. coli genome and proteome database

Saccharomyces Genome Database

UCSC Genome Bioinformatics

Errol Friedberg's homepage

Glossary

SOS RESPONSE

A transcriptional response to DNA damage or arrested replication in prokaryotes, during which numerous repressed genes are derepressed, resulting in increased numbers of several proteins involved in various aspects of DNA repair and mutagenesis.

XERODERMA PIGMENTOSUM (XP)

A hereditary disease characterized by a marked predisposition to skin cancer due to either defective nucleotide excision repair or the absence of functional Polη.

NUCLEOTIDE EXCISION REPAIR

A mode of DNA repair during which damaged bases are excised from the genome as components of oligonucleotide fragments.

MONOUBIQUITYLATION

A process during which a single ubiquitin moiety is covalently bound to a particular lysine residue in a protein.

AP SITES

Sites of base loss in DNA, which results in the generation of apurinic or apyrimidinic regions in the genome.

BRCT MOTIF

A protein motif with homology to the C-terminal region of the BRCA1 tumour supressor protein.

EPISTASIS

The interaction of several gene products in a common biochemical pathway, usually defined by genetic analysis.

E2 ENZYME

An enzyme that accepts ubiquitin or a ubiquitin-like protein from an E1 enzyme and transfers it to the substrate, mostly using an E3 enzyme.

RING-FINGER DOMAIN

A protein domain that consists of two loops that are held together at their base by Cys and His residues that form a complex with two zinc ions. Many RING fingers function in protein degradation by facilitating protein ubiquitylation.

POLYUBIQUITYLATION

A process similar to monoubiquitylation in which a chain of several ubiquitin moieties are added to a different lysine residue in a protein.

PRIMOSOME

A complex of proteins, the role of which is to initiate DNA synthesis by de novo synthesis of an oligonucleotide RNA primer on a DNA template strand. A primosome is typically used to initiate synthesis at a replication origin or to re-initiate synthesis downstream of a stalled replication fork.

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Friedberg, E. Suffering in silence: the tolerance of DNA damage. Nat Rev Mol Cell Biol 6, 943–953 (2005). https://doi.org/10.1038/nrm1781

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