Nature Genetics37, 193 - 197 (2005)
Published online: 23 January 2005; | doi:10.1038/ng1506
Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage
Paul S Bradshaw1, 2, 4, Dimitrios J Stavropoulos1, 2, 4
& M Stephen Meyn1, 2, 3
1
Program in Genetics and Genomic Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
2
Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
3
Department of Paediatrics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
4
These authors contributed equally to this work.
Correspondence should be addressed to M Stephen Meyn meyn@sickkids.ca
DNA damage surveillance networks in human cells can activate DNA repair, cell cycle checkpoints and apoptosis in response to fewer than four double-strand breaks (DSBs) per genome1,
2. These same networks tolerate telomeres, in part because the protein TRF2 prevents recognition of telomeric ends as DSBs3 by facilitating their organization into T loops4,
5,
6. We now show that TRF2 associates with photo-induced DSBs in nontelomeric DNA in human fibroblasts within 2 s of irradiation. Unlike H2AX, a common marker for DSB damage, TRF2 forms transient foci that colocalize closely with DSBs. The TRF2 DSB response requires the TRF2 basic domain but not its Myb domain and occurs in the absence of functional ATM and DNA-PK protein kinases, MRE11/Rad50/NBS1 complex and Ku70, WRN and BLM repair proteins. Furthermore, overexpression of TRF2 inhibits DSB-induced phosphorylation of ATM signaling targets. Our results implicate TRF2 in an initial stage of DSB recognition and processing that occurs before association of ATM with DSBs and activation of the ATM-dependent DSB response network.
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H2AX, a common marker for DSB damage, TRF2 forms transient foci that colocalize closely with DSBs. The TRF2 DSB response requires the TRF2 basic domain but not its Myb domain and occurs in the absence of functional ATM and DNA-PK protein kinases, MRE11/Rad50/NBS1 complex and Ku70, WRN and BLM repair proteins. Furthermore, overexpression of TRF2 inhibits DSB-induced phosphorylation of ATM signaling targets. Our results implicate TRF2 in an initial stage of DSB recognition and processing that occurs before association of ATM with DSBs and activation of the ATM-dependent DSB response network.
