Abstract
The DNA damage response (DDR) is a complex signaling network that relies on cascades of protein phosphorylation, which are initiated by three protein kinases of the family of PI3-kinase-related protein kinases (PIKKs): ATM, ATR, and DNA-PK. ATM is missing or inactivated in the genome instability syndrome, ataxia-telangiectasia (A-T). The relative shares of these PIKKs in the response to genotoxic stress and the functional relationships among them are central questions in the genome stability field. We conducted a comprehensive phosphoproteomic analysis in human wild-type and A-T cells treated with the double-strand break-inducing chemical, neocarzinostatin, and validated the results with the targeted proteomic technique, selected reaction monitoring. We also matched our results with 34 published screens for DDR factors, creating a valuable resource for identifying strong candidates for novel DDR players. We uncovered fine-tuned dynamics between the PIKKs following genotoxic stress, such as DNA-PK-dependent attenuation of ATM. In A-T cells, partial compensation for ATM absence was provided by ATR and DNA-PK, with distinct roles and kinetics. The results highlight intricate relationships between these PIKKs in the DDR.
Original language | English |
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Article number | e104400 |
Journal | EMBO Journal |
Volume | 40 |
Issue number | 2 |
Early online date | 20 Nov 2020 |
DOIs | |
State | Published - 15 Jan 2021 |
Keywords
- ATM
- DNA damage response
- PIKKs
- ataxia-telangiectasia
- phosphoproteomics
All Science Journal Classification (ASJC) codes
- General Immunology and Microbiology
- General Biochemistry,Genetics and Molecular Biology
- Molecular Biology
- General Neuroscience