DNA damage-induced phosphorylation of the human telomere-associated protein TRF2.
Several protein kinases from diverse eukaryotes known to perform important roles in DNA repair have also been shown to play critical roles in telomere maintenance. Here, we report that the human telomere-associated protein TRF2 is rapidly phosphorylated in response to DNA damage. We find that the phosphorylated form of TRF2 is not bound to telomeric DNA, as is the ground form of TRF2, and is rapidly localized to damage sites. Our results suggest that the ataxia-telangiectasia-mutated (ATM) protein kinase signal-transduction pathway is primarily responsible for the DNA damage-induced phosphorylation of TRF2. Unlike DNA damage-induced phosphorylation of other ATM targets, the phosphorylated form of TRF2 is transient, being detected rapidly at DNA damage sites postirradiation, but largely dissipated by 2 hours. In addition, we report that the phosphorylated form of TRF2 is present at telomeres in cell types undergoing telomere-based crisis and a recombination-driven, telomerase-independent, alternative lengthening of telomeres (ALT) pathway, likely as a consequence of a telomere-based DNA damage response. Our results link the induction of TRF2 phosphorylation to the DNA damage-response system, providing an example of direct cross-talk via a signaling pathway between these two major cellular processes essential for genomic stability, telomere maintenance, and DNA repair.
Tanaka
Hiromi
H
Departments of Medical and Molecular Genetics, Radiation Oncology, and Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Mendonca
Marc S
MS
Bradshaw
Paul S
PS
Hoelz
Derek J
DJ
Malkas
Linda H
LH
Meyn
M Stephen
MS
Gilley
David
D
D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D008666:Metalloendopeptidases; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015398:Signal Transduction; D035182:TATA Box Binding Protein-Like Proteins / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2; D025521:Tumor Suppressor Proteins / Q000502:physiology
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D035182:TATA Box Binding Protein-Like Proteins; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D008666:Metalloendopeptidases; C070738:O-sialoglycoprotein endopeptidase