Letter abstract
Nature Cell Biology 8, 416 - 424 (2006)
Published online: 26 March 2006 | doi:10.1038/ncb1386
DNA methyltransferases control telomere length and telomere recombination in mammalian cells
Susana Gonzalo1, Isabel Jaco1, Mario F. Fraga2, Taiping Chen3, En Li3, Manel Esteller2 & María A. Blasco1
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.
- Epigenetics Group, Molecular Pathology Program, Spanish National Cancer Centre (CNIO), Madrid E-28029, Spain.
- Epigenetics Program, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Correspondence to: María A. Blasco1 e-mail: mblasco@cnio.es
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