Does a sentinel or a subset of short telomeres determine replicative senescence?

Ying Zou, Agnel Sfeir, Sergei M. Gryaznov, Jerry W. Shay, Woodring E. Wright

Research output: Contribution to journalArticle

191 Scopus citations

Abstract

The proliferative life span of human cells is limited by telomere shortening, but the specific telomeres responsible for determining the onset of senescence have not been adequately determined. We here identify the shortest telomeres by the frequency of signal-free ends after in situ hybridization with telomeric probes and demonstrate that probes adjacent to the shortest ends colocalize with γH2AX-positive DNA damage foci in senescent cells. Normal BJ cells growth arrest at senescence before developing significant karyotypic abnormalities. We also identify all of the telomeres involved in end-associations in BJ fibroblasts whose cell-cycle arrest at the time of replicative senescence has been blocked and demonstrate that the 10% of the telomeres with the shortest ends are involved in >90% of all end-associations. The failure to find telomeric end-associations in near-senescent normal BJ metaphases, the presence of signal-free ends in 90% of near-senescent metaphases, and the colocalization of short telomeres with DNA damage foci in senescent interphase cells suggests that end-associations rather than damage signals from short telomeres per se may be the proximate cause of growth arrest. These results demonstrate that a specific group of chromosomes with the shortest telomeres rather than either all or only one or two sentinel telomeres is responsible for the induction of replicative senescence.

Original languageEnglish (US)
Pages (from-to)3709-3718
Number of pages10
JournalMolecular biology of the cell
Volume15
Issue number8
DOIs
StatePublished - Aug 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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