The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response Journal Article
| Authors: | Karlseder, J.; Hoke, K.; Mirzoeva, O. K.; Bakkenist, C.; Kastan, M. B.; Petrini, J. H. J.; De Lange, T. |
| Article Title: | The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response |
| Abstract: | The telomeric protein TRF2 is required to prevent mammalian telomeres from activating DNA damage checkpoints. Here we show that overexpression of TRF2 affects the response of the ATM kinase to DNA damage. Overexpression of TRF2 abrogated the cell cycle arrest after ionizing radiation and diminished several other readouts of the DNA damage response, including phosphorylation of Nbs1, induction of p53, and upregulation of p53 targets. TRF2 inhibited autophosphorylation of ATM on S1981, an early step in the activation of this kinase. A region of ATM containing S1981 was found to directly interact with TRF2 in vitro, and ATM immunoprecipitates contained TRF2. We propose that TRF2 has the ability to inhibit ATM activation at telomeres. Because TRF2 is abundant at chromosome ends but not elsewhere in the nucleus, this mechanism of checkpoint control could specifically block a DNA damage response at telomeres without affecting the surveillance of chromosome internal damage. |
| Keywords: | controlled study; protein phosphorylation; unclassified drug; dna binding protein; human cell; dna-binding proteins; protein localization; cell cycle protein; chromosome; telomere; metabolism; mammalia; cell cycle proteins; dna damage; cell cycle; gene overexpression; enzyme inhibition; nuclear protein; protein protein interaction; protein targeting; protein binding; enzyme activation; cell line, tumor; transfection; protein serine threonine kinase; autophosphorylation; phosphorylation; protein p53; physiology; dna strand breakage; nuclear proteins; dna; genetic transfection; protein-serine-threonine kinases; tumor suppressor proteins; tumor cell line; glutathione transferase; immunoprecipitation; immunoblotting; atm protein; ionizing radiation; protein induction; radiation, ionizing; tumor suppressor protein p53; binding protein; dimerization; upregulation; up-regulation; tumor suppressor protein; ultrastructure; chromosomes; protein synthesis inhibition; mitosis inhibition; humans; human; article; telomeric protein trf 2; nbs1 protein, human; tata binding protein related factor; trf2 protein, human; tata box binding protein-like proteins |
| Journal Title: | PLoS Biology |
| Volume: | 2 |
| Issue: | 8 |
| ISSN: | 1544-9173 |
| Publisher: | Public Library of Science |
| Date Published: | 2004-08-01 |
| Start Page: | e240 |
| Language: | English |
| DOI: | 10.1371/journal.pbio.0020240 |
| PROVIDER: | scopus |
| PMCID: | PMC509302 |
| PUBMED: | 15314656 |
| DOI/URL: | |
| Notes: | PloS Biol. -- Cited By (since 1996):171 -- Export Date: 16 June 2014 -- CODEN: PBLIB -- Source: Scopus |
