Nucleic Acids Research Advance Access originally published online on August 5, 2009
Nucleic Acids Research 2009 37(18):6225-6238; doi:10.1093/nar/gkp629
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Nucleic Acids Research, 2009, Vol. 37, No. 18 6225-6238
© 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.
Genome Integrity, Repair and Replication |
Human telomeres that contain (CTAGGG)n repeats show replication dependent instability in somatic cells and the male germline
1Department of Genetics, University of Leicester, Leicester, LE1 7RH, UK, 2School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore and 3INSERM U565, CNRS UMR 7196, USM 503, Muséum National d’Histoire Naturelle, 43 rue Cuvier, 75005 Paris, France
*To whom correspondence should be addressed. Tel: +44 0116 252 2270; Fax: +44 0116 252 3378; Email: njr{at}le.ac.uk
Received May 12, 2009. Revised June 25, 2009. Accepted July 14, 2009.
A number of different processes that impact on telomere length dynamics have been identified but factors that affect the turnover of repeats located proximally within the telomeric DNA are poorly defined. We have identified a particular repeat type (CTAGGG) that is associated with an extraordinarily high mutation rate (20% per gamete) in the male germline. The mutation rate is affected by the length and sequence homogeneity of the (CTAGGG)n array. This level of instability was not seen with other sequence-variant repeats, including the TCAGGG repeat type that has the same composition. Telomeres carrying a (CTAGGG)n array are also highly unstable in somatic cells with the mutation process resulting in small gains or losses of repeats that also occasionally result in the deletion of the whole (CTAGGG)n array. These sequences are prone to quadruplex formation in vitro but adopt a different topology from (TTAGGG)n (see accompanying article). Interestingly, short (CTAGGG)2 oligonucleotides induce a DNA damage response (
H2AX foci) as efficiently as (TTAGGG)2 oligos in normal fibroblast cells, suggesting they recruit POT1 from the telomere. Moreover, in vitro assays show that (CTAGGG)n repeats bind POT1 more efficiently than (TTAGGG)n or (TCAGGG)n. We estimate that 7% of human telomeres contain (CTAGGG)n repeats and when present, they create additional problems that probably arise during telomere replication.
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  K. W. Lim, P. Alberti, A. Guedin, L. Lacroix, J.-F. Riou, N. J. Royle, J.-L. Mergny, and A. T. Phan Sequence variant (CTAGGG)n in the human telomere favors a G-quadruplex structure containing a G{middle dot}C{middle dot}G{middle dot}C tetrad Nucleic Acids Res., October 1, 2009; 37(18): 6239 - 6248. [Abstract] [Full Text] [PDF]
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