ATR inhibition rewires cellular signaling networks induced by replication stress. Issue 3 (February 2016)

• Record Type: Journal Article
• Authors: Wagner, Sebastian A.; Oehler, Hannah; Voigt, Andrea; Dalic, Denis; Freiwald, Anja; Serve, Hubert; Beli, Petra
• Is Part Of: Proteomics. Volume 16:Issue 3(2016)
• Page Start: 402
• Page End: 416
• Publication Date: 2016-02
• Subjects: ATR kinase -- Cancer -- DNA replication stress -- Phosphoproteomics -- Quantitative MS -- Systems biology; Proteins -- Separation -- Periodicals; Bioinformatics -- Periodicals; Proteomics -- Periodicals; Genomes -- Periodicals; Molecular genetics -- Periodicals; 572.605
• DOI: 10.1002/pmic.201500172
• Languages: English
• ISSNs: 1615-9853

Abstract

Abstract : The slowing down or stalling of replication forks is commonly known as replication stress and arises from multiple causes such as DNA lesions, nucleotide depletion, RNA‐DNA hybrids, and oncogene activation. The ataxia telangiectasia and Rad3‐related kinase (ATR) plays an essential role in the cellular response to replication stress and inhibition of ATR has emerged as therapeutic strategy for the treatment of cancers that exhibit high levels of replication stress. However, the cellular signaling induced by replication stress and the substrate spectrum of ATR has not been systematically investigated. In this study, we employed quantitative MS‐based proteomics to define the cellular signaling after nucleotide depletion‐induced replication stress and replication fork collapse following ATR inhibition. We demonstrate that replication stress results in increased phosphorylation of a subset of proteins, many of which are involved in RNA splicing and transcription and have previously not been associated with the cellular replication stress response. Furthermore, our data reveal the ATR‐dependent phosphorylation following replication stress and discover novel putative ATR target sites on MCM6, TOPBP1, RAD51AP1, and PSMD4. We establish that ATR inhibition rewires cellular signaling networks induced by replication stress and leads to the activation of the ATM‐driven double‐strand break repair signaling.