Hyper telomere recombination accelerates replicative senescence and may promote premature aging

R. Tanner Hagelstrom, Krastan B. Blagoev, Laura J. Niedernhofer, Edwin H. Goodwin, Susan M. Bailey

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Werner syndrome and Bloom syndrome result from defects in the RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and display premature aging phenotypes. Similarly, XFE progeroid syndrome results from defects in the ERCC1-XPF DNA repair endonuclease. To gain insight into the origin of cellular senescence and human aging, we analyzed the dependence of sister chromatid exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telomeric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, BLM, or ERCC1-XPF. Consistent with our other studies, we found evidence of elevated T-SCE in telomerase-negative but not telomerasepositive backgrounds. In telomerase-negative WRN-deficient cells, T-SCE - but not G-SCE - frequencies were significantly increased compared with controls. In contrast, SCE frequencies were significantly elevated in BLM-deficient cells irrespective of genome location. In ERCC1-XPF-deficient cells, neither T- nor G-SCE frequencies differed from controls. A theoretical model was developed that allowed an in silico investigation into the cellular consequences of increased T-SCE frequency. The model predicts that in cells with increased T-SCE, the onset of replicative senescence is dramatically accelerated even though the average rate of telomere loss has not changed. Premature cellular senescence may act as a powerful tumor-suppressor mechanism in telomerase-deficient cells with mutations that cause T-SCE levels to rise. Furthermore, T-SCE-driven premature cellular senescencemay be a factor contributing to accelerated aging in Werner and Bloom syndromes, but not XFE progeroid syndrome.

Original languageEnglish (US)
Pages (from-to)15768-15773
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number36
DOIs
StatePublished - Sep 7 2010
Externally publishedYes

Keywords

  • BLM
  • ERCC1-XPF
  • Monte carlo
  • T-SCE
  • WRN

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