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DNA polymerases and cancer

Key Points

  • Fifteen DNA polymerases are encoded in mammalian genomes. Some function in the replication of the genome, but most participate in specialized DNA repair and DNA damage tolerance processes. The activity of these DNA polymerases will affect the response of a cell to DNA-damaging carcinogens and chemotherapeutic agents.

  • Some DNA polymerases catalyse DNA synthesis on damaged sites in DNA, helping cells tolerate DNA damage by translesion DNA synthesis (TLS). TLS polymerases are specialized for the bypass of different DNA adducts. Defects in Pol η (also known as POLH) are responsible for the variant type of xeroderma pigmentosum (XP-V).

  • Pol ζ (the catalytic subunit of which is REV3L) and REV1 are required for nearly all damage-induced base change mutagenesis in mammalian cells. Reduction of their activities sensitizes cells, including tumour cells, to DNA-damaging agents. However, chromosome rearrangements and inflammation can increase in the absence of these proteins, promoting carcinogenesis.

  • The expression of some genes encoding DNA polymerases may be altered in some cancers. In breast cancers, levels of POLQ (which encodes Pol θ) seem to be the most elevated compared with normal levels of expression. Comprehensive studies of DNA polymerase protein levels in cancer remain to be carried out.

  • The inhibition of DNA polymerase activities could be useful as an adjuvant to DNA-damaging therapies, and inhibitors for some polymerases have been found. Pharmacologically effective inhibitors highly specific for a single DNA polymerase remain to be identified.

  • Whole-genome analyses of cancers have not yet revealed cancer-associated alterations in DNA polymerase genes. It seems likely, however, that at least some cells in a tumour will have relevant alterations. Some DNA polymerases can be considered as tumour suppressors (Pol ζ, REV1, Pol η, Pol ι, Pol κ, Pol δ and Pol ɛ).

Abstract

There are 15 different DNA polymerases encoded in mammalian genomes, which are specialized for replication, repair or the tolerance of DNA damage. New evidence is emerging for lesion-specific and tissue-specific functions of DNA polymerases. Many point mutations that occur in cancer cells arise from the error-generating activities of DNA polymerases. However, the ability of some of these enzymes to bypass DNA damage may actually defend against chromosome instability in cells, and at least one DNA polymerase, Pol ζ, is a suppressor of spontaneous tumorigenesis. Because DNA polymerases can help cancer cells tolerate DNA damage, some of these enzymes might be viable targets for therapeutic strategies.

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Figure 1: DNA damage tolerance and carcinogenesis.
Figure 2: Strategies for translesion DNA synthesis.

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Acknowledgements

Research on DNA polymerases by the authors is supported by US National Institutes of Health (NIH) grants CA09717 and CA132840 from the National Cancer Institute, by grant P30ES007784 from the National Institute of Environmental Health Sciences and by NIH Cancer Center Support Grant P30-CA016672 (University of Texas MD Anderson Cancer Center, USA).

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Correspondence to Richard D. Wood.

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DATABASES

National Cancer Institute Drug Dictionary

bleomycin

cisplatin

cyclophosphamide

eicosapentaenoic acid

etoposide

hydroxyurea

mitomycin C

oxaliplatin

temozolomide

FURTHER INFORMATION

Human DNA Repair Genes

Glossary

DNA damage

A term that encompasses the many types of chemical alterations that can change the structure of DNA. Damage can be caused by reactions that disrupt bonds in the nucleobases, the deoxyribose sugar ring, or the phosphate groups of DNA or by the addition of chemical moieties such as hydroxyl groups, methyl groups, or even bulkier groups derived from polycyclic molecules. Such additions are often referred to as DNA adducts. DNA damage is already plural, so DNA damages is incorrect, an alternative is DNA lesions.

Template switching

An error-avoiding strategy for DNA damage tolerance that uses the newly synthesized, undamaged strand of a sister chromatid for bypass replication.

Checkpoint

A control mechanism to verify whether each phase of the cell cycle has been completed accurately. If DNA damage is present, some checkpoint controls prevent or delay progression through the cell cycle, for example from G1 to S phase or from G2 phase to mitosis.

Leading and lagging strands

DNA synthesis can only add nucleotides to the terminal 3′-OH group of a growing polymer. The strand synthesized continuously during DNA replication is the leading strand. The strand of DNA that is synthesized in discontinuous segments is the lagging strand.

Exonuclease

An exonuclease cleaves DNA phosphodiester bonds to release nucleotides from one end of a polynucleotide chain. DNA polymerases synthesize DNA in a 5′–3′ direction and some DNA polymerases have an intrinsic 3′–5′ exonuclease activity that enables proofreading of their own mistakes.

Y-family

The prototypes for Y-family polymerases are the Escherichia coli TLS DNA polymerases DinB (Pol IV) and UmuC (Pol V).

B-family

B-family DNA polymerases show similarity to E. coli Pol II.

A-family

The A-family DNA polymerase domain is similar to E. coli DNA polymerase I (Pol I), encoded by the bacterial PolA gene.

Xeroderma pigmentosum

An inherited human syndrome characterized by severe photosensitivity, a high incidence of skin cancer and neurological abnormalities. The disorder is caused by a deficiency in NER genes (XPA-XPG), or in TLS past UV radiation-induced DNA damage (the XP-V type is caused by mutations in POLH).

Cyclobutane pyrimidine dimer

(CPD). The most frequent UV radiation-induced DNA lesion, formed by the covalent linkage of the C5 and C6 bonds of adjacent pyrimidines to form a cyclobutane ring, without directly altering the base pairing faces of the dimerized bases. Such dimers are formed most commonly between adjacent thymines, but also between thymine and cytosine or two adjacent cytosines.

Fragile site

Heritable regions on chromosomes that are associated with an increased frequency of chromosome breaks, gaps and other aberrations. Fragile sites, and the genes that they contain, are frequently rearranged or deleted in cancer cells.

(6-4) photoproduct

The second most common type of UV radiation-induced DNA damage, involving linkage of the C6 position of a 5′ pyrimidine base to the C4 position of a 3′ adjacent pyrimidine base. (6-4) photoproducts distort the DNA helix more than a CPD and form most often at 5′ thymine-cytosine-3′ sequences.

Abasic site

A site in a DNA chain that is missing a pyrimidine or purine base residue, but where the phosphodiester backbone remains intact. Such sites can arise when a base–sugar bond is cleaved by a DNA glycosylase during BER, or by a spontaneous hydrolytic reaction.

Interstrand crosslink

(ICL). Covalently links the two complementary strands of duplex DNA. Such crosslinks are formed by some carcinogenic and chemotherapeutic agents and they are especially toxic because they block the complementary DNA strand separation that is necessary for DNA replication and transcription.

Sliding clamp

A mobile platform for DNA replication and repair machinery. The eukaryotic sliding clamp PCNA binds to DNA polymerases and is crucial for the switching of polymerases during TLS and DNA repair.

X-family

X-family polymerases in mammalian cells are Pol β, Pol λ, Pol μ and TDT.

Hydrolytic reactions

Decomposition of a chemical compound or a molecular bond by reaction with water.

Alkylating agent

An electrophilic compound that can covalently add an alkyl group to a DNA base, or to other biological macromolecules. These compounds act as both carcinogens (for example, methyl chloride) and as chemotherapeutic agents (for example, mechloroethamine).

Nonsense mutation

A change in the codon for an amino acid to a stop codon. Nonsense mutations cause protein truncation and often nonsense-mediated decay of the encoding mRNA.

Terminal deoxynucleotidyl-transferase

(TDT). A template-independent DNA synthesis activity that catalyses the addition of nucleotides to the 3′ terminus end of DNA. The TDT enzyme in human cells contributes to immune diversity by adding nucleotides of varying lengths between gene segments during V(D)J recombination.

V(D)J recombination

Assembles immunoglobulin and T cell receptor genes from different segments. The RAG1–RAG2 nuclease introduces DNA DSBs to produce segments that are joined by NHEJ.

Micronuclei

Pieces of DNA that reside outside of the nucleus, caused by chromosome breakage leading to accentric chromosome fragments that lack spindle attachments, or by chromosome mis-segregation during mitosis. Micronuclei are most easily detected in mature erythrocytes that lack nuclear DNA.

Ribozyme

A catalytic enzyme made entirely of RNA. Some ribozymes are nucleases and can include base-pairing regions that enable specific binding and cleavage of a target RNA molecule.

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Lange, S., Takata, Ki. & Wood, R. DNA polymerases and cancer. Nat Rev Cancer 11, 96–110 (2011). https://doi.org/10.1038/nrc2998

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