DNA hypomethylation leads to elevated mutation rates

Abstract

Genome-wide demethylation has been suggested to be a step in carcinogenesis. Evidence for this notion comes from the frequently observed global DNA hypomethylation in tumour cells, and from a recent study suggesting that defects in DNA methylation might contribute to the genomic instability of some colorectal tumour cell lines. DNA hypomethylation has also been associated with abnormal chromosomal structures, as observed in cells from patients with ICF (Immunodeficiency, Centromeric instability and Facial abnormalities) syndrome and in cells treated with the demethylating agent 5-azadeoxycytidine. 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.

Dynamic and reversibility of heterochromatic gene silencing in human disease

“…3) an increase of mutation rates for exogenous marker genes in ES cells and an increase of losing heterozygosity due to mitotic recombination [16]; 4) enhanced microsatellite instability in mouse embryonic stem cells [17]; 5) demethylation and expression of transposons of the intracisternal A particle (IAP) class, the LTR retroposons [18][19][20] attributing to the specific role of DNMT1 in gene silencing on transposable elements; 6) very high rates of lethal T-cell lymphomas [21].…”

Artificial light-at-night – a novel lifestyle risk factor for metabolic disorder and cancer morbidity

“…Global hypomethylation in white blood cells has also been reported to be related with increased risk of breast cancer [170,171]. Global DNA hypo-methylation can promote breast cancer development via several signaling pathways, including triggering genomic instability, activation of oncogenes, and inducing metastasis formations [172,173]. Furthermore, GDM levels revealed positive correlation with carcinogenic clinical characteristics including, stage of the cancer, tumor growth rates, and high grade [160,174,175].…”

Epigenetic aspects of MDS and its molecular targeted therapy

“…Specific modifications (denoted by small green, orange, and red circles) to the amino acids (denoted by gray circles) of these histones' tails occur 5mC content was found to reach an average of 10 % [22], and affected repetitive elements and specific gene promoters [23,24]. Although the cause of this demethylation remains unclear, marked loss of 5mC was shown to be associated with chromosomal breaks, genomic instabilities, increased mutation rates, and reactivation of normally silenced genes [23,25]. Alongside global DNA hypomethylation, many genes have been shown to demonstrate de novo DNA methylation, especially at their promoters [2].…”