A new function for ATM and a new theory for the clinical abnormalities in A-T
Research Project information
Principal researcher: Professor Mike Kastan
Institute: Duke University, North Carolina, USA
Cost: £249,854 over 36 months
Completion date: 31st December 2023
Project Overview
Ataxia Telangiectasia (A-T), results from loss of function of the ATM (Ataxia Telangiectasia, Mutated) gene. Although much is known about the function of the protein encoded by this gene, mechanistic understanding of how loss of the gene’s function leads to the presentation of the disease, including neurodegeneration, cancer, lung abnormalities, etc, remains incomplete. Further understanding of ATM regulation and function is needed to help show how loss of ATM affects cellular processes and the clinical presentation of the disease. This study built on previous work and aimed to explore the interaction of ATM and a gene called SMG1 to characterise signal pathways between them.
Research Methods and Outcome
The gene SMG1 is in the same protein family as ATM and the team made the unexpected observation that ATM protein is required for controlling SMG1 protein activity after being exposed to DNA damaging agents, like ionizing radiation. They found that ATM helps control production of alternative forms of the DNA damage-responsive and tumour suppressive protein p53, in part through negative regulation SMG1 activity. These alternative versions of p53 protein that are produced in response to irradiation in ATM intact cells, unlike in cells that have lost ATM, promote the senescence (growth arrest) of cells and triggers production of a pro-inflammatory environment around cells. They showed that ATM and SMG1 contribute to cellular senescence through the production of these alternative versions of p53 protein. They also identified another protein, DDX5, that is required for production of the alternative versions of the p53 protein and for control of cellular senescence after irradiation. In all, ATM, SMG1, and DDX5 work to promote irradiation-induced cellular senescence through production of alternative versions of the DNA damage-responsive protein p53. Alterations in this signalling pathway may contribute to the neuronal and cancer abnormalities seen in A-T patients.
While not all experiments that were proposed in the original application were successful (mainly those related to the specific biochemical mechanisms by which ATM regulates SMG1 kinase activity), the project was successful in meeting the overall objectives by formally demonstrating the role of ATM in regulating SMG1, in identifying an additional novel and interesting component of this signalling pathway (the RNA helicase, DDX5), and in demonstrating that this pathway affects a very important A-T phenotype, namely cellular senescence.
What next?
The researchers are keen to explore these unexpected new insights further and plan further work to analyse whether these new pathways could potentially account for important A-T clinical phenotypes, particularly the neurodegeneration.
Publications
McCann JJ, Fleenor DE, Chen J, Lai C-H, Bass TE, Kastan MB. Participation of ATM, SMG1, and DDX5 in a DNA Damage-induced Alternative Splicing Pathway. Radiation Research, 199: 406-421, 2023. PMID: 36921295 DOI: 10.1667/RADE-22-00219.1
