POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end

Dirk Hockemeyer, Agnel J. Sfeir, Jerry W. Shay, Woodring E. Wright, Titia De Lange

Research output: Contribution to journalArticle

211 Citations (Scopus)

Abstract

The hallmarks of telomere dysfunction in mammals are reduced telomeric 3′ overhangs, telomere fusions, and cell cycle arrest due to a DNA damage response. Here, we report on the phenotypes of RNAi-mediated inhibition of POT1, the single-stranded telomeric DNA-binding protein. A 10-fold reduction in POT1 protein in tumor cells induced neither telomere fusions nor cell cycle arrest. However, the 3′ overhang DNA was reduced and all telomeres elicited a transient DNA damage response in G1, indicating that extensive telomere damage can occur without cell cycle arrest or telomere fusions. RNAi to POT1 also revealed its role in generating the correct sequence at chromosome ends. The recessed 5′ end of the telomere, which normally ends on the sequence ATC-5′, was changed to a random position within the AATCCC repeat. Thus, POT1 determines the structure of the 3′ and 5′ ends of human chromosomes, and its inhibition generates a novel combination of telomere dysfunction phenotypes in which chromosome ends behave transiently as sites of DNA damage, yet remain protected from nonhomologous end-joining.

Original languageEnglish (US)
Pages (from-to)2667-2678
Number of pages12
JournalEMBO Journal
Volume24
Issue number14
DOIs
StatePublished - Jul 20 2005

Fingerprint

Telomere
Human Chromosomes
Chromosomes
DNA Damage
Cells
Fusion reactions
DNA
Cell Cycle Checkpoints
Mammals
DNA-Binding Proteins
RNA Interference
Joining
Tumors
Phenotype
Proteins

Keywords

  • POT1
  • POT1-55
  • Telomerase
  • Telomere
  • TRF2

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. / Hockemeyer, Dirk; Sfeir, Agnel J.; Shay, Jerry W.; Wright, Woodring E.; De Lange, Titia.

In: EMBO Journal, Vol. 24, No. 14, 20.07.2005, p. 2667-2678.

Research output: Contribution to journalArticle

Hockemeyer, Dirk ; Sfeir, Agnel J. ; Shay, Jerry W. ; Wright, Woodring E. ; De Lange, Titia. / POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. In: EMBO Journal. 2005 ; Vol. 24, No. 14. pp. 2667-2678.
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