Dataset Information

Phosphoproteomics reveals novel modes of function and inter-relationships among PIKKs in response to genotoxic stress.

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.

SUBMITTER: Schlam-Babayov S

PROVIDER: S-EPMC7809795 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Phosphoproteomics reveals novel modes of function and inter-relationships among PIKKs in response to genotoxic stress.

Schlam-Babayov Sapir S Bensimon Ariel A Harel Michal M Geiger Tamar T Aebersold Ruedi R Ziv Yael Y Shiloh Yosef Y

The EMBO journal 20201120 2

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 fie ...[more]

PMID: 33215756

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Dataset Information

Phosphoproteomics reveals novel modes of function and inter-relationships among PIKKs in response to genotoxic stress.

Publications

Phosphoproteomics reveals novel modes of function and inter-relationships among PIKKs in response to genotoxic stress.

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