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Human telomeres that contain (CTAGGG)n repeats show replication dependent instability in somatic cells and the male germline

By Aaron Mendez-Bermudez, Mark Hills, Hilda A. Pickett, Anh Tuân Phan, Jean-Louis Mergny, Jean-François Riou and Nicola J. Royle


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 (γH2AX 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

Publisher: Oxford University Press (OUP)
Year: 2009
DOI identifier: 10.1093/nar
OAI identifier:

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  1. (1996). A comprehensive genetic map of the human genome based on 5,264 microsatellites. doi
  2. (2002). A high-resolution recombination map of the human genome. doi
  3. (2003). Analysis of thermal melting curves. doi
  4. (2007). Circular dichroism of quadruplex DNAs: applications to structure, cation effects and ligand binding. doi
  5. (1997). Comparison of the human and mouse genes encoding the telomeric protein, TRF1: chromosomal localization, expression and conserved protein domains. Human Mol. doi
  6. (2004). DNA binding features of human POT1: a nonamer 50-TAG GGTTAG-30 minimal binding site, sequence specificity, and internal binding to multimeric sites. doi
  7. (2008). Evidence for alternative lengthening of telomeres in liposarcomas in the absence of ALT-associated PML bodies. doi
  8. (1998). Following G-quartet formation by UV-spectroscopy. doi
  9. France) for generous gift of POT1, TRF1 and TRF2, A. Gue´din and J.L. Lacroix (Muse´um Paris) for helpful discussions. Medical Research Council (UK) (grant G0500336 to N.J.R.); Cancer Research-UK (grant
  10. (1997). Further evidence for elevated human minisatellite mutation rate in Belarus eight years after the Chernobyl accident. doi
  11. (2000). Heterogeneous mutation processes in human microsatellite DNA sequences.
  12. (2000). High levels of sequence polymorphism and linkage disequilibrium at the telomere of 12q: implications for telomere biology and human evolution. doi
  13. (2008). How shelterin protects mammalian telomeres. doi
  14. (2007). How telomeres are replicated. doi
  15. (2005). Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro. doi
  16. (2006). Human replication protein A unfolds telomeric G-quadruplexes. doi
  17. (2007). Human telomere, oncogenic promoter and 50-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics. doi
  18. (1989). Human telomeres contain at least 3 types of G-rich repeat distributed non-randomly. doi
  19. (1997). Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. doi
  20. (2008). Mcm4 C-terminal domain of MCM helicase prevents excessive formation of single-stranded DNA at stalled replication forks. doi
  21. (2008). Measured and calculated CD spectra of G-quartets stacked with the same or opposite polarities. doi
  22. (1995). Mechanisms underlying telomere repeat turnover, revealed by hypervariable variant repeat distribution patterns in the human Xp/Yp telomere.
  23. (1995). Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. doi
  24. (2004). Microsatellites: simple sequences with complex evolution. doi
  25. (2004). MSH2-dependent germinal CTG repeat expansions are produced continuously in spermatogonia from DM1 transgenic mice. doi
  26. (2007). Non-B DNA conformations, mutagenesis and disease. doi
  27. (2001). Pot1, the putative telomere end-binding protein in fission yeast and humans. doi
  28. (1997). Relative mutation rates at di-, tri-, and tetranucleotide microsatellite loci. doi
  29. (2005). Repeat instability: mechanisms of dynamic mutations. doi
  30. (2007). Replication and protection of telomeres. doi
  31. (2005). Replication fork dynamics and dynamic mutations: the fork-shift model of repeat instability. doi
  32. (2008). Sequence effects in single-base loops for quadruplexes. doi
  33. (2009). Sequence variant (CTAGGG)n in the human telomere favors a G-quadruplex structure containing a GCGC tetrad. doi
  34. (2003). Slipping while sleeping? Trinucleotide repeat expansions in germ cells. doi
  35. (2008). ssDNA fragments induce cell senescence by telomere uncapping. doi
  36. (2004). Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. doi
  37. (2004). Telomere instability detected in sporadic colon cancers, some showing mutations in a mismatch repair gene. doi
  38. (2000). The direction of microsatellite mutations is dependent upon allele length.
  39. (2006). The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. doi
  40. (1999). The plasticity of human telomeres demonstrated by a hypervariable telomere repeat array that is located on some copies of 16p and 16q. doi
  41. (2005). Thermal difference spectra: a specific signature for nucleic acid structures. doi

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