Journal Article

Activation of the ALT pathway for telomere maintenance can affect other sequences in the human genome

Jennie N. Jeyapalan, Helen Varley, Jenny L. Foxon, Raphael E. Pollock, Alec J. Jeffreys, Jeremy D. Henson, Roger R. Reddel and Nicola J. Royle

in Human Molecular Genetics

Volume 14, issue 13, pages 1785-1794
Published in print July 2005 | ISSN: 0964-6906
Published online May 2005 | e-ISSN: 1460-2083 | DOI:
Activation of the ALT pathway for telomere maintenance can affect other sequences in the human genome

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Immortal human cells maintain telomere length by the expression of telomerase or through the alternative lengthening of telomeres (ALT). The ALT mechanism involves a recombination-like process that allows the rapid elongation of shortened telomeres. However, it is not known whether activation of the ALT pathway affects other sequences in the genome. To address this we have investigated, in ALT-expressing cell lines and tumours, the stability of tandem repeat sequences known to mutate via homologous recombination in the human germline. We have shown extraordinary somatic instability in the human minisatellite MS32 (D1S8) in ALT-expressing (ALT+) but not in normal or telomerase-expressing cell lines. The MS32 mutation frequency varied across 15 ALT+ cell lines and was on average 55-fold greater than in ALT− cell lines. The MS32 minisatellite was also highly unstable in three of eight ALT+ soft tissue sarcomas, indicating that somatic destabilization occurs in vivo. The MS32 mutation rates estimated for two ALT+ cell lines were similar to that seen in the germline. However, the internal structures of ALT and germline mutant alleles are very different, indicating differences in the underlying mutation mechanisms. Five other hypervariable minisatellites did not show elevated instability in ALT-expressing cell lines, indicating that minisatellite destabilization is not universal. The elevation of MS32 instability upon activation of the ALT pathway and telomere length maintenance suggests there is overlap between the underlying processes that may be tractable through analysis of the D1S8 locus.

Journal Article.  6256 words.  Illustrated.

Subjects: Genetics and Genomics

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