Hyper telomere recombination accelerates replicative senescence and may promote premature aging.
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 telomerase-positive 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 senescence may be a factor contributing to accelerated aging in Werner and Bloom syndromes, but not XFE progeroid syndrome.
Hagelstrom
R Tanner
RT
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, 80523-1618, USA.
Blagoev
Krastan B
KB
Niedernhofer
Laura J
LJ
Goodwin
Edwin H
EH
Bailey
Susan M
SM
D019588:Aging, Premature / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D005090:Exodeoxyribonucleases / Q000235:genetics; D006801:Humans; D051379:Mice; D053484:RecQ Helicases / Q000235:genetics; D011995:Recombination, Genetic; D012854:Sister Chromatid Exchange; D016615:Telomere; D000071657:Werner Syndrome Helicase
D004268:DNA-Binding Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; D005090:Exodeoxyribonucleases; C097151:Bloom syndrome protein; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase
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