DNA methyltransferases control telomere length and telomere recombination in mammalian cells.
Here, we describe a role for mammalian DNA methyltransferases (DNMTs) in telomere length control. Mouse embryonic stem (ES) cells genetically deficient for DNMT1, or both DNMT3a and DNMT3b have dramatically elongated telomeres compared with wild-type controls. Mammalian telomere repeats (TTAGGG) lack the canonical CpG methylation site. However, we demonstrate that mouse subtelomeric regions are heavily methylated, and that this modification is decreased in DNMT-deficient cells. We show that other heterochromatic marks, such as histone 3 Lys 9 (H3K9) and histone 4 Lys 20 (H4K20) trimethylation, remain at both subtelomeric and telomeric regions in these cells. Lack of DNMTs also resulted in increased telomeric recombination as indicated by sister-chromatid exchanges involving telomeric sequences, and by the presence of 'alternative lengthening of telomeres' (ALT)-associated promyelocytic leukaemia (PML) bodies (APBs). This increased telomeric recombination may lead to telomere-length changes, although our results do not exclude a potential involvement of telomerase and telomere-binding proteins in the aberrant telomere elongation observed in DNMT-deficient cells. Together, these results demonstrate a previously unappreciated role for DNA methylation in maintaining telomere integrity.
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid E-28029, Spain.
Susana
S
Gonzalo
Isabel
I
Jaco
Mario F
MF
Fraga
Taiping
T
Chen
En
E
Li
Manel
M
Esteller
María A
MA
Blasco
D000818:Animals; D022003:Cell Nucleus Structures / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D020541:Coiled Bodies / Q000235:genetics / Q000378:metabolism; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D011995:Recombination, Genetic; D012854:Sister Chromatid Exchange; D013234:Stem Cells / Q000378:metabolism; D016615:Telomere / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D006570:Heterochromatin; D000097584:DNA Methyltransferase 3B; C000715535:Dnmt3a protein, mouse; C000619381:Dnmt1 protein, mouse