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Abstract 241: A mutant DNA polymerase-delta associated with increased tumor progression causes random deletions in DNA

2010; American Association for Cancer Research; Volume: 70; Issue: 8_Supplement Linguagem: Inglês

10.1158/1538-7445.am10-241

1538-7445

Lawrence A. Loeb, Michael Schmitt, Ranga N. Venkatesan, Marie‐Jeanne Pillaire, Jean‐Sébastien Hoffmann,

Genomics and Rare Diseases

Abstract For many years, we have advanced the hypothesis that cancers exhibit a mutator phenotype. Recent support for this concept was gained by the increased frequency of random single-base substitutions measured in human tumors as well as by the large numbers of clonal mutations detected by DNA sequencing in a variety of human cancers. While these findings indicate that cancer cells accumulate large numbers of mutations, it remains unclear what types of alterations in the fidelity of DNA synthesis contribute most to the evolution of a tumor. In order to delineate the types of mutations that have the greatest impact on accelerating tumorigenesis, we studied the consequences of altered accuracy of synthesis by mutant DNA polymerases. DNA polymerase δ (Pol δ) is responsible for replication of the lagging DNA strand during replication and functions in multiple DNA repair pathways. Based on homology to substitutions known to induce error-prone synthesis in other DNA polymerases, we constructed a series of single base substitutions at position L606 in the catalytic domain of human Pol δ. We found that Pol δ L606G introduces a high frequency of point mutations into DNA in vitro, but heterozygous mice expressing L606G do not exhibit a cancer phenotype. In contrast, Pol δ L606K synthesizes DNA in vitro with high accuracy; yet heterozygous mice expressing this mutant exhibit enhanced rates of tumor progression. Compared to either the wild type or L606G, the L606K mutant is defective in lesion bypass; cells expressing this mutant exhibit a decrease in the rate of fork progression. In addition, L606K cells exhibit an increase in spontaneous chromosomal aberrations, and comparative genomic hybridization analysis reveals an increased frequency of random deletions in tumors from mice expressing Pol δ L606K. These results indicate that mutations in a major replicating DNA polymerase can result in random deletions throughout the genome that have the potential to affect tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 241.