Abstract
Protein kinases of the phosphatidylinositol 3-kinase-like kinase family, originally known to act in maintaining genomic integrity via DNA repair pathways, have been shown to also function in telomere maintenance. Here we focus on the functional role of DNA damage-induced phosphorylation of the essential mammalian telomeric DNA binding protein TRF2, which coordinates the assembly of the proteinaceous cap to disguise the chromosome end from being recognized as a double-stand break (DSB). Previous results suggested a link between the transient induction of human TRF2 phosphorylation at threonine 188 (T188) by the ataxia telangiectasia mutated protein kinase (ATM) and the DNA damage response. Here, we report evidence that X-ray-induced phosphorylation of TRF2 at T188 plays a role in the fast pathway of DNA DSB repair. These results connect the highly transient induction of human TRF2 phosphorylation to the DNA damage response machinery. Thus, we find that a protein known to function in telomere maintenance, TRF2, also plays a functional role in DNA DSB repair.
ACKNOWLEDGMENTS
We thank John Turchi for assistance in performing the Comet assay analysis. We thank Anna Malkova, John Turchi, and Junya Kobayashi for valuable comments during the preparation of the manuscript. We thank Helen Chin-Sinex for valuable technical support during X-ray exposures.
This work was supported by the Indiana University Cancer Center, the American Cancer Society, the Showalter Foundation, the Susan G. Komen Foundation, the Avon Foundation, and the Indiana Genomics Initiative (INGEN). INGEN of Indiana University is supported in part by Lilly Endowment Inc.