Erosion of the telomeric single-strand overhang at replicative senescence

Sheila A. Stewart, Ittai Ben-Porath, Vincent J. Carey, Benjamin F. O'Connor, William C. Hahn, Robert A. Weinberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

281 Scopus citations

Abstract

Cultured primary human cells inevitably enter a state of replicative senescence for which the specific molecular trigger is unknown. We show that the single-strand telomeric overhang, a key component of telomere structure, is eroded at senescence. Expression of telomerase prevents overhang loss, suggesting that this enzyme prevents senescence by maintaining proper telomere structure. In contrast, progressive overhang loss occurs in cells that avoid senescence through the inactivation of p53 and Rb, indicating that overhang erosion is the result of continuous cell division and not a consequence of senescence. We thus provide evidence for a specific molecular alteration in telomere structure at senescence and suggest that this change, rather than overall telomere length, serves to trigger this state.

Original languageAmerican English
Pages (from-to)492-496
Number of pages5
JournalNature Genetics
Volume33
Issue number4
DOIs
StatePublished - 1 Apr 2003
Externally publishedYes

Bibliographical note

Funding Information:
We would like to thank E. D’Ambrosio for helpful advice regarding T-OLA and for sharing unpublished results, F. Barany for repeated helpful advice, T. de Lange and J. Griffith for plasmids and K. Yates, Y. Dor, J. Yang, R. Watnick, P. Gupta, H. Vaziri, S. Dessain and other members of R.A.W.’s laboratory for helpful comments, discussion and critical review of the manuscript. This work was supported by Merck/MIT (R.A.W.), the US National Cancer Institute (R.A.W.), an American Association for Cancer Research Postdoctoral Fellowship (S.A.S.), an EMBO Long-Term Fellowship (I.B.), the Dana Farber Cancer Institute (V.J.C.), the US National Cancer Institute Howard Temin award (W.C.H.), a Doris Duke Charitable Foundation Clinical Scientist Development Award (W.C.H.) and a Kimmel Scholar Award (W.C.H.). R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor.

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