Related Experiment Video
Updated: Feb 6, 2026
Assaying Protein Kinase Activity with Radiolabeled ATP
Published on: May 26, 2017
Homeodomain Proteins Directly Regulate ATM Kinase Activity
Tanya E Johnson1, Ji-Hoon Lee1, Logan R Myler1
1Department 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.
Abstract:
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.
Insights
Homeodomain proteins regulate the DNA damage response by interacting with ATM kinase. This interaction influences ATM activity, suggesting a novel mechanism for controlling DNA repair during development and differentiation.
Area of Science:
- Molecular Biology
- Genetics
- Cellular Biology
Background:
- Ataxia-telangiectasia mutated (ATM) is a key kinase coordinating responses to DNA double-strand breaks and oxidative stress.
- NKX3.1, a prostate-specific transcription factor, was previously identified to stimulate ATM kinase activity via its homeodomain.
Purpose of the Study:
- To investigate whether other homeodomain family members can regulate ATM kinase activity.
- To elucidate the interaction between homeodomain proteins, ATM, and the MRN complex in DNA damage response pathways.
Main Methods:
- Co-immunoprecipitation assays to assess physical interactions between homeodomain proteins and ATM/MRN complex.
- In vitro kinase assays to measure ATM activity under various conditions.
- Cell-based assays in human cells to evaluate functional consequences.
Main Results:
- Six representative homeodomain proteins (NKX3.1, NKX2.2, TTF1, NKX2.5, HOXB7, CDX2) were found to physically and functionally interact with both ATM and the MRN complex.
- Binding of homeodomain proteins to ATM stimulated oxidation-induced ATM activation in vitro.
- Conversely, this binding inhibited ATM kinase activity in the presence of MRN and DNA, and within human cells.
Conclusions:
- Tissue-specific homeodomain proteins can modulate ATM kinase activity.
- This interaction represents a unique regulatory mechanism for the DNA damage response, particularly during development and differentiation.
Related Concept Videos
02:54Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
02:54Protein Kinases and Phosphatases
02:58Regulated Protein Degradation
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
02:58Regulated Protein Degradation
02:04Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein....
02:04Covalently Linked Protein Regulators