Nucleic Acids Research Advance Access originally published online on January 7, 2009
Nucleic Acids Research 2009 37(4):1152-1159; doi:10.1093/nar/gkn1030
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Nucleic Acids Research, 2009, Vol. 37, No. 4 1152-1159
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Telomerase activity is associated with an increase in DNA methylation at the proximal subtelomere and a reduction in telomeric transcription
1Victor Chang Cardiac Research Institute, Darlinghurst 2010, 2Faculty of Medicine, The University of New South Wales, Kensington 2052 and 3Children's Medical Research Institute, Westmead 2145, Australia
*To whom correspondence should be addressed. Tel: +61 2 92 95 87 20; Fax: +61 2 92 95 86 01; Email: c.suter{at}victorchang.edu.au Correspondence may also be addressed to Roger R. Reddel. Tel: +61 2 88 65 28 00; Fax: +61 2 88 65 28 60; Email: rreddel{at}cmri.usyd.edu.au
Received November 6, 2008. Revised December 9, 2008. Accepted December 10, 2008.
Tumours and immortalized cells avoid telomere attrition by using either the ribonucleoprotein enzyme telomerase or a recombination-based alternative lengthening of telomeres (ALT) mechanism. Available evidence from mice suggests that the epigenetic state of the telomere may influence the mechanism of telomere maintenance, but this has not been directly tested in human cancer. Here we investigated cytosine methylation directly adjacent to the telomere as a marker of the telomere's epigenetic state in a panel of human cell lines. We find that while ALT cells show highly heterogeneous patterns of subtelomeric methylation, subtelomeric regions in telomerase-positive cells invariably show denser methylation than normal cells, being almost completely methylated. When compared to matched normal and ALT cells, telomerase-positive cells also exhibit reduced levels of the telomeric repeat-containing-RNA (TERRA), whose transcription originates in the subtelomere. Our results are consistent with the notion that TERRA may inhibit telomerase: the heavy cytosine methylation we observe in telomerase-positive cells may reflect selection for TERRA silencing in order to facilitate telomerase activity at the telomere. These data suggest that the epigenetic differences between telomerase-positive and ALT cells may underlie the mechanism of telomere maintenance in human tumorigenesis and highlight the broad reaching consequences of epigenetic dysregulation in cancer.
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