Pot1 and cell cycle progression cooperate in telomere length regulation

Nat Struct Mol Biol. 2008 Jan;15(1):79-84. doi: 10.1038/nsmb1331. Epub 2007 Dec 9.

Abstract

Removal of the vertebrate telomere protein Pot1 results in a DNA damage response and cell cycle arrest. Here we show that loss of chicken Pot1 causes Chk1 activation, and inhibition of Chk1 signaling prevents the cell cycle arrest. However, arrest still occurs after disruption of ATM, which encodes another DNA damage response protein. These results indicate that Pot1 is required to prevent a telomere checkpoint mediated by another such protein, ATR, that is most likely triggered by the G-overhang. We also show that removal of Pot1 causes exceptionally rapid telomere growth upon arrest in late S/G2 of the cell cycle. However, release of the arrest slows both telomere growth and G-overhang elongation. Thus, Pot1 seems to regulate telomere length and G-overhang processing both through direct interaction with the telomere and by preventing a late S/G2 delay in the cell cycle. Our results reveal that cell cycle progression is an important component of telomere length regulation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Androstadienes / pharmacology
  • Ataxia Telangiectasia Mutated Proteins
  • Caffeine / pharmacology
  • Carbazoles / pharmacology
  • Cell Cycle / drug effects
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • G2 Phase
  • Humans
  • Indoles / pharmacology
  • Kinetics
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • S Phase
  • Tamoxifen / pharmacology
  • Telomere / chemistry
  • Telomere / physiology*
  • Telomere-Binding Proteins / deficiency
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / physiology*
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Wortmannin

Substances

  • Androstadienes
  • Carbazoles
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Indoles
  • POT1 protein, human
  • Telomere-Binding Proteins
  • Tumor Suppressor Proteins
  • Tamoxifen
  • Go 6976
  • Caffeine
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Wortmannin