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DNA hypomethylation leads to elevated mutation rates

Abstract

Genome-wide demethylation has been suggested to be a step in carcinogenesis1. Evidence for this notion comes from the frequently observed global DNA hypomethylation in tumour cells2, and from a recent study suggesting that defects in DNA methylation might contribute to the genomic instability of some colorectal tumour cell lines3. DNA hypomethylation has also been associated with abnormal chromosomal structures, as observed in cells from patients with ICF (Immunodeficiency, Centromeric instability and Facial abnormalities) syndrome4,5 and in cells treated with the demethylating agent 5-azadeoxycytidine6. Here we report that murine embryonic stem cells nullizygous for the major DNA methyltransferase (Dnmt1) gene exhibited significantly elevated mutation rates at both the endogenous hypoxanthine phosphoribosyltransferase (Hprt) gene and an integrated viral thymidine kinase (tk) transgene. Gene deletions were the predominant mutations at both loci. The major cause of the observed tk deletions was either mitotic recombination or chromosomal loss accompanied by duplication of the remaining chromosome. Our results imply an important role for mammalian DNA methylation in maintaining genome stability.

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Figure 1: Analysis of Hprt mutations in the 6-TG-resistant ES clones.
Figure 2: Creation of a hemizygous HSV–tk transgene locus and analysis of tk mutations in ganciclovir-resistant ES cells.
Figure 3

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Acknowledgements

We thank P. P. Lee for pMT-3lox; W. M. Rideout III, and J. T. Lee for critical reading of the manuscript; and W. Thilly for helpful discussion. This work was supported by a grant from the swedish Medical Research Council (U.P.), postdoctoral fellowships from the Ann Fuller Fund (R.Z.C.) and the Cancer Research Fund of the Damon Runyon–Walter Winchell Foundation (L.J.-G.), and by the National Institutes of Health (R.Z.C., L.J.-G. and R.J.)

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Correspondence to Rudolf Jaenisch.

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Chen, R., Pettersson, U., Beard, C. et al. DNA hypomethylation leads to elevated mutation rates. Nature 395, 89–93 (1998). https://doi.org/10.1038/25779

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