Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA; Howard Hughes Medical Institute, The University of Texas at Austin, Austin, TX 78712, USA
Ji-Hoon Lee
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA; Howard Hughes Medical Institute, The University of Texas at Austin, Austin, TX 78712, USA
Logan R. Myler
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA; Howard Hughes Medical Institute, The University of Texas at Austin, Austin, TX 78712, USA
Yi Zhou
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
Trenell J. Mosley
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
Soo-Hyun Yang
College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712, USA
Nadima Uprety
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
Jonghwan Kim
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
Tanya T. Paull
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA; Howard Hughes Medical Institute, The University of Texas at Austin, Austin, TX 78712, USA; Corresponding author
Summary: Ataxia-telangiectasia mutated (ATM) is a serine/threonine kinase that coordinates the response to DNA double-strand breaks and oxidative stress. NKX3.1, a prostate-specific transcription factor, was recently shown to directly stimulate ATM kinase activity through its highly conserved homeodomain. Here, we show that other members of the homeodomain family can also regulate ATM kinase activity. We found that six representative homeodomain proteins (NKX3.1, NKX2.2, TTF1, NKX2.5, HOXB7, and CDX2) physically and functionally interact with ATM and with the Mre11-Rad50-Nbs1 (MRN) complex that activates ATM in combination with DNA double-strand breaks. The binding between homeodomain proteins and ATM stimulates oxidation-induced ATM activation in vitro but inhibits ATM kinase activity in the presence of MRN and DNA and in human cells. These findings suggest that many tissue-specific homeodomain proteins may regulate ATM activity during development and differentiation and that this is a unique mechanism for the control of the DNA damage response. : Johnson et al. demonstrate that several members of the homeobox transcription factor family bind directly to the ATM protein kinase and to the MRN complex, inhibiting activation of ATM by DNA double-strand breaks. These results suggest that homeobox proteins may act as tissue-specific regulators of the DNA damage response. Keywords: ATM, DNA damage response, DNA double-strand breaks, homeodomain proteins, MRN
