期刊
EMBO JOURNAL
卷 40, 期 2, 页码 -出版社
WILEY
DOI: 10.15252/embj.2020104400
关键词
ataxia-telangiectasia; ATM; DNA damage response; phosphoproteomics; PIKKs
资金
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Israel Cancer Research Fund
- Tel Aviv University Global Research and Training Fellowship (GRTF) by the Naomi Prawer Kadar Foundation
- Swiss National Science Foundation [31003A_166435]
- SystemsX.ch, the Swiss Initiative for Systems Biology
- Swiss National Science Foundation (SNF) [31003A_166435] Funding Source: Swiss National Science Foundation (SNF)
This study conducted a comprehensive phosphoproteomic analysis in human wild-type and A-T cells to reveal the fine-tuned dynamics and relationships between PIKKs in the response to genotoxic stress. The results highlight the complex interactions among ATM, ATR, and DNA-PK in the DDR.
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.
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