DNA methyltransferases control telomere length and telomere recombination in mammalian cells

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Abstract

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.

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Figure 1: Deregulation of telomere length in ES cells deficient for DNA methyltransferase activities.
Figure 2: Decreased DNA methylation levels in cells lacking DNA methyltransferase activities.
Figure 3: Subtelomeric and telomeric chromatin features of DNMT-deficient ES cells.
Figure 4: Increased telomeric sister-chromatid exchange in DNMT-deficient cells.
Figure 5: Increased APBs in DNMT-deficient cells.

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Acknowledgements

S.G. is a Fondo de Investigaciones Sanitarias (FIS) senior scientist. I. J. is a student of the Gulbenkian PhD Program in Biomedicine and is supported by Fundacão para la Ciěncia e Tecnologia/Ministério da Ciěncia e Ensino Superior (FCT/MCT; Portugal). M.E. is funded by the Ministry of Science and Technology of Spain (MCYT; T08-03) and the European Union (CCEE04-00). M.A.B. is funded by the MCYT (SAF2005-00277, GEN2001-4856-C13-08), the regional government of Madrid (GR/SAL/0597/2004), the European Union (TELOSENS FIGH-CT-2002-00217, INTACT LSHC-CT-2003-506803, ZINCAGE FOOD-CT-2003-506850, RISC-RAD FI6R-CT-2003-508842) and the Josef Steiner Cancer Research Award 2003.

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Correspondence to María A. Blasco.

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The authors declare no competing financial interests.

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Supplementary Information

Supplementary Figures S1, S2, S3, Table 1 and Supplementary Text (PDF 673 kb)

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Gonzalo, S., Jaco, I., Fraga, M. et al. DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 8, 416–424 (2006) doi:10.1038/ncb1386

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