ATR-mediated proteome remodeling is a major determinant of homologous recombination capacity in cancer cells

Nucleic Acids Research
Dongsung KimMarcus B Smolka

Abstract

The ATR kinase is crucial for genome maintenance, but the mechanisms by which ATR controls the DNA repair machinery are not fully understood. Here, we find that long-term chronic inhibition of ATR signaling severely impairs the ability of cells to utilize homologous recombination (HR)-mediated DNA repair. Proteomic analysis shows that chronic ATR inhibition depletes the abundance of key HR factors, suggesting that spontaneous ATR signaling enhances the capacity of cells to use HR-mediated repair by controlling the abundance of the HR machinery. Notably, ATR controls the abundance of HR factors largely via CHK1-dependent transcription, and can also promote stabilization of specific HR proteins. Cancer cells exhibit a strong dependency on ATR signaling for maintaining elevated levels of HR factors, and we propose that increased constitutive ATR signaling caused by augmented replication stress in cancer cells drives the enhanced HR capacity observed in certain tumor types. Overall, these findings define a major pro-HR function for ATR and have important implications for therapy by providing rationale for sensitizing HR-proficient cancer cells to PARP inhibitors.

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Citations

Aug 9, 2019·The EMBO Journal·Michael Charles LanzMarcus Bustamante Smolka
Mar 17, 2020·Annual Review of Biochemistry·David P WatermanMarcus B Smolka
Apr 26, 2019·Journal of Hematology & Oncology·Lin MeiJingsong Zhang
Jan 14, 2020·Genetics and Molecular Biology·José Renato Rosa CussiolFrancisco Meirelles Bastos de Oliveira
Aug 29, 2020·Genes·Huanbo ZhuJun Zhang
Dec 13, 2018·Nucleic Acids Research·Helga B LandsverkRandi G Syljuåsen
Sep 10, 2020·Frontiers in Oncology·Katharina HintelmannThorsten Rieckmann
Jan 9, 2021·Frontiers in Cell and Developmental Biology·Paula Andrea MarinMaria Carolina Elias
Aug 1, 2019·Trends in Cell Biology·Andrea K ByrumNima Mosammaparast
Apr 4, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Zhengke LiYue Zou
Jul 31, 2021·Current Opinion in Genetics & Development·Antoine Simoneau, Lee Zou

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Datasets Mentioned

BETA
GM18366
PXD010223

Methods Mentioned

BETA
chromosomal aberrations
flow cytometry
transfection
PCR

Software Mentioned

Slidebook
lightcycler 480
Sorcerer

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