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

The EMBO Journal
Sapir Schlam-BabayovYosef Shiloh

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.

References

Apr 16, 1998·The Journal of Biological Chemistry·E P RogakouW M Bonner
Jun 8, 2001·Molecular and Cellular Biology·H Zhao, H Piwnica-Worms
Jan 17, 2004·Biochimie·S P Lees-Miller, K Meek
Feb 13, 2007·Nature Methods·Bernd BodenmillerRuedi Aebersold
Jun 16, 2007·Cell·Rune LindingTony Pawson
Nov 17, 2007·Science·Nadine K KolasDaniel Durocher
Dec 14, 2007·Proceedings of the National Academy of Sciences of the United States of America·Matthew P StokesMichael J Comb
May 26, 2009·DNA Repair·Courtney A Lovejoy, David Cortez
Nov 6, 2009·Proceedings of the National Academy of Sciences of the United States of America·Courtney A LovejoyDavid Cortez
Feb 19, 2010·Molecular & Cellular Proteomics : MCP·Martin V BennetzenJens S Andersen
Oct 13, 2010·Proceedings of the National Academy of Sciences of the United States of America·Danny M ChouStephen J Elledge
Oct 16, 2010·Trends in Biochemical Sciences·Rachel Litman Flynn, Lee Zou
Dec 9, 2010·Science Signaling·Ariel BensimonYosef Shiloh
Jan 6, 2011·Science Signaling·Shu Kondo, Norbert Perrimon
Jan 25, 2011·Journal of Proteome Research·Jürgen CoxMatthias Mann
Jun 4, 2011·EMBO Reports·Tobias MenzelClaus Storgaard Sørensen
Aug 8, 2012·The Journal of Cell Biology·Yosef Shiloh, Yael Ziv

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Citations

Feb 19, 2021·Matrix Biology : Journal of the International Society for Matrix Biology·Thomas Juretschke, Petra Beli
Apr 17, 2021·Molecular & Cellular Oncology·Sapir Schlam-BabayovYosef Shiloh
Aug 26, 2021·Nature Reviews. Molecular Cell Biology·Ji-Hoon Lee, Tanya T Paull

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