Translesion DNA replication proteins as molecular targets for cancer prevention

Watson, Nicholas B.; Mukhopadhyay, Suparna; McGregor, W. Glenn

doi:10.1016/j.canlet.2005.10.013

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Volume 241, Issue 1 , Pages 13-22, 8 September 2006

Translesion DNA replication proteins as molecular targets for cancer prevention

Nicholas B. Watson
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA
- Nicholas B. Watson and Suparna Mukhopadhyay contributed equally to this work.
Suparna Mukhopadhyay
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA
- Nicholas B. Watson and Suparna Mukhopadhyay contributed equally to this work.
W. Glenn McGregor
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA
- Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY, USA
- Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
- Corresponding author. Address: Department of Pharmacology and Toxicology, University of Louisville, 221A Baxter 1 Biomedical Research, 570 S. Preston Street, Louisville, KY 40202, USA. Tel.: +1 502 852 2564; fax: +1 502 852 2492.

Received 15 September 2005; received in revised form 10 October 2005; accepted 13 October 2005.

Abstract

Mutations in DNA are generally considered to have an etiologic role in the development of cancer. If so, it follows that reducing the frequency of such mutations will reduce the incidence of cancer induced by mutagens. Recent advances in elucidating the molecular mechanisms of carcinogen-induced mutagenesis indicate that replication of DNA templates that contain replication-blocking adducts is accomplished with error-prone DNA polymerases. These polymerases have relaxed base-pairing requirements, and can insert bases across from adducted templates, but with potentially mutagenic consequences. In principle, these proteins present new and attractive molecular targets to reduce mutagenesis. If this can be done in vivo without increasing cytotoxic responses to carcinogens, then novel chemopreventive strategies can be designed to reduce the risk of cancer in exposed populations prior to the appearance of disease symptoms.

Keywords: Mutagenesis, Translesion DNA synthesis, RAD18, REV1, UV, BPDE