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  • Review Article
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DNA polymerases and human disease

Nature Reviews Genetics volume 9, pages 594–604 (2008)Cite this article

Key Points

  • DNA polymerases carry out crucial functions in many DNA metabolic processes.

  • Polymerases catalyse the addition, using a template, of complementary nucleotides to the 3′ end of DNA primer strands. Many DNA polymerases also have an additional intrinsic proofreading exonuclease activity.

  • The high accuracy or fidelity of semi-conservative DNA replication is the product of nucleotide template interaction, polymerase-enhanced base selectivity, exonuclease proofreading and the post-replication mismatch repair of misincorporated nucleotides.

  • Cells contain at least 13 documented DNA polymerases that might have different functions.

  • The five earliest-identified DNA polymerases (α, β, δ, ε and γ) are essential proteins that have key roles in nuclear DNA- or mitochondrial DNA-mediated transactions.

  • Recently identified 'specialized' or translesion synthesis (TLS) polymerases supplement the activities of the five 'canonical' polymerases to replicate or facilitate the repair of damaged DNA.

  • Polymerase expression and activity are highly regulated in cells during development by genetic and epigenetic mechanisms.

  • There are few human diseases that have been linked to mutations or defects in DNA polymerases. Mutations in the polymerase that replicates mitochondrial DNA, Pol γ, lead to a range of human neuromuscular and ophthalmologic diseases. Loss of function of the TLS polymerase Pol η leads to xeroderma pigmentosum-variant, a DNA repair and cancer predisposition syndrome.

  • Heritable or acquired variation in DNA polymerases might be important in human disease, especially in age-associated proliferative diseases such as cancer.

  • DNA polymerases are under-exploited therapeutic targets for the treatment of infectious disease and acquired human diseases involving cell proliferation — most notably cancer.

Abstract

The human genome encodes at least 14 DNA-dependent DNA polymerases — a surprisingly large number. These include the more abundant, high-fidelity enzymes that replicate the bulk of genomic DNA, together with eight or more specialized DNA polymerases that have been discovered in the past decade. Although the roles of the newly recognized polymerases are still being defined, one of their crucial functions is to allow synthesis past DNA damage that blocks replication-fork progression. We explore the reasons that might justify the need for so many DNA polymerases, describe their function and mode of regulation, and finally consider links between mutations in DNA polymerases and human disease.

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Figure 1: Classical DNA polymerases and associated subunits.
Figure 2: DNA polymerase catalysis and structure.
Figure 3: Fidelity of DNA replication.
Figure 4: DNA polymerase expression and activity in cycling cells and whole organisms.

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Acknowledgements

We are grateful to A. Blank, J. Sidorova and A.S. Mildvan for comments. Research in the laboratories of the authors are supported by National Institutes of Health Grants: CA 77852 to R.M. & L.A.L., CA 102029 and CA 115802 to L.A.L., and CA 13383 to R.M.

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Authors and Affiliations

  1. Department of Pathology University of Washington, K-072 HSB, BOX 357705, Seattle, 98195-7705, Washington DC, USA

    Lawrence A. Loeb & Raymond J. Monnat Jr

  2. Gottstein Memorial Cancer Research Laboratory, University of Washington, Seattle, 98195, Washington DC, USA

    Lawrence A. Loeb

  3. Department of Biochemistry, University of Washington, Seattle, 98195, Washington DC, USA

    Lawrence A. Loeb

  4. Department of Genome Sciences, University of Washington, Seattle, 98195, Washington DC, USA

    Raymond J. Monnat Jr

Authors
  1. Lawrence A. Loeb
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  2. Raymond J. Monnat Jr
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FURTHER INFORMATION

The Monnat laboratory homepage

Lawrence Loeb's homepage

miRNABase Targets database

Catalogue of Somatic Mutations in Cancer (COSMIC) database

Segmental Duplication Database

NCBI Cancer Chromosomes database

NCBI SNP database (dbSNP)

NCI Cancer Genome Anatomy Project

UK Sanger Institute Cancer Genome Project

USCS Genome Browser

Glossary

Lagging strand

One of the two DNA strands that is synthesized during DNA replication. The lagging strand is synthesized by Pol δ in short segments that are known as Okasaki fragments.

Leading strand

One of the two DNA strands that is synthesized during DNA replication. The leading strand is believed to be synthesized by Pol ε, predominantly in a single segment.

Non-processive

Processivity refers to the number of nucleotide additions per binding event between DNA polymerase and a DNA template. Non-processive DNA polymerases incorporate one or a few base pairs per DNA-binding event. Processive DNA polymerases incorporate thousands of nucleotides per DNA-binding event.

Holoenzyme

The catalytically active form of DNA polymerases, including all tightly bound associated subunits.

Homoplasmic

The presence of identical copies of mitochondrial DNA in a cell or tissue.

Haploinsufficient

Describes the situation in which half the amount of the normal gene product confers a detectable phenotype.

Nucleotide adduct

A covalent modification of a nucleotide base in DNA.

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Loeb, L., Monnat, R. DNA polymerases and human disease. Nat Rev Genet 9, 594–604 (2008). https://doi.org/10.1038/nrg2345

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  • DOI: https://doi.org/10.1038/nrg2345

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