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Normal mammalian cells negatively regulate telomere length by telomere trimming.

Authors
  • Pickett, Hilda A
  • Henson, Jeremy D
  • Au, Amy Y M
  • Neumann, Axel A
  • Reddel, Roger R
Type
Published Article
Journal
Human Molecular Genetics
Publisher
Oxford University Press
Publication Date
Dec 01, 2011
Volume
20
Issue
23
Pages
4684–4692
Identifiers
DOI: 10.1093/hmg/ddr402
PMID: 21903669
Source
Medline
License
Unknown

Abstract

In human cancer cells with telomeres that have been over-lengthened by exogenous telomerase activity, telomere shortening can occur by a process that generates circles of double-stranded telomeric DNA (t-circles). Here, we demonstrate that this telomeretrimming process occurs in cells of the male germline and in normal lymphocytes following mitogen-stimulated upregulation of telomerase activity. Mouse tissues also contain abundant t-circles, suggesting that telomere trimming also contributes to telomere length regulation in mice. In cancer cells and stimulated lymphocytes, the mechanism involves the XRCC3 homologous recombination (HR) protein and generates single-stranded C-rich telomeric DNA. This suggests that, in addition to the well-documented gradual telomere attrition that accompanies cellular replication, there is also a more rapid form of negative telomere length control in normal mammalian cells, which most likely involves HR-mediated removal of telomere loops in the form of t-circles. We therefore propose that this telomere trimming mechanism is an additional factor in the balance between telomere lengthening and telomere shortening in normal human germline and somatic cells that may prevent excessive lengthening by processes such as telomerase activity.

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