Abstract
Mice null for the Pms2 mismatch repair (MMR) gene exhibit a predisposition to lymphoma, microsatellite repeat instability, and failure of spermatogenesis. To study the role of Pms2 in the maintenance of in vivo genomic integrity in somatic cells, we characterized Aprt mutations in T cells and fibroblasts of 129×C3H Pms2−/−Aprt+/− mice. The spontaneous frequency of DAP-resistant T lymphocytes, as a consequence of APRT-deficiency, was increased threefold. Point mutation, which accounted for less than 20% of the DAPr mutant clones in Pms2+/+ mice, was predominant in the mutant T cell clones from Pms2−/− mice. These point mutations were predominantly TA to CG transitions. Fibroblasts of Pms2−/− mice exhibited only a modest increase in the frequency of clones with point mutations, such that mitotic recombination was still the primary cause of APRT deficiency. Thus, the mutator phenotype as a consequence of PMS2 deficiency is tissue-dependent, which may be related to the tissue-specific tumor proneness of Pms2−/− mice.
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Acknowledgements
We thank RM Liskay for generously providing us with Pms2 knockout mice. This work was supported by grants from NIH (R01DK38185, P01ES05652 and P30ES05022).
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Shao, C., Yin, M., Deng, L. et al. Loss of heterozygosity and point mutation at Aprt locus in T cells and fibroblasts of Pms2−/− mice. Oncogene 21, 2840–2845 (2002). https://doi.org/10.1038/sj.onc.1205358
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DOI: https://doi.org/10.1038/sj.onc.1205358