Journal Article

Candidate mutator genes in mismatch repair-deficient thymic lymphomas: no evidence of mutations in the DNA polymerase δ gene

Marcia R. Campbell, Thy Y. Thang, Frank R. Jirik and Susan E. Andrew

in Carcinogenesis

Volume 21, issue 12, pages 2281-2285
Published in print December 2000 | ISSN: 0143-3334
Published online December 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.12.2281
Candidate mutator genes in mismatch repair-deficient thymic lymphomas: no evidence of mutations in the DNA polymerase δ gene

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DNA mismatch repair (MMR) proteins recognize nucleotides that are incorrectly paired. Deficiencies in MMR lead to increased genomic instability reflected in an increased mutation frequency and predisposition to tumorigenesis. Mice lacking the MMR gene, Msh2, develop thymic lymphomas that exhibit much higher mutational frequencies than other Msh2–/– tumours and Msh2–/– normal thymic tissue, suggesting that an additional mutator may have been acquired in a tissue-specific manner. Clustered mutations observed exclusively in the thymic lymphomas suggests that a gene(s) associated with the replication machinery might have become altered during tumorigenesis. Based on mutation studies in Saccharomyces cerevisiae lacking Msh2 and DNA polymerase δ (DNA pol δ), we hypothesized that the acquisition of mutations in DNA pol δ could contribute to the hypermutator phenotype and tumorigenesis in Msh2–/– thymic tissue. Furthermore, previous reports have suggested that genes containing mononucleotide repeats are non-random mutational targets in the absence of MMR. Therefore, we sequenced all 26 exons of the DNA pol δ catalytic subunit, including the six exons containing mononucleotide repeats of >5 bp, from nine Msh2–/– thymic lymphomas and two wild-type controls. No DNA pol δ pathogenic mutations were found in the thymic lymphomas, although several DNA base differences compared with published DNA pol δ sequences were observed. We conclude, therefore, that inactivating mutations in DNA pol δ are not a contributing factor in the development of the hypermutator phenotype in MMR-deficient murine thymic lymphomas.

Keywords: DNA pol δ; DNA polymerase δ; MMR, mismatch repair; PCR, polymerase chain reaction.

Journal Article.  3193 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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