Proteomics

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ATR inhibition rewires cellular signaling networks in response to pathologic replication stress

ABSTRACT: DNA replication stress is the major cause of genomic instability in human cells. 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 cancer. However, the ATR-dependent signaling in the cellular response to replication stress has not been systematically investigated. Here, we employ quantitative mass spectrometry-based proteomics to decipher the ATR-dependent phosphorylation events in response to pathological replication stress induced by hydroxyurea. Our data define the substrate spectrum of ATR and identify several novel putative ATR substrates. In addition, we demonstrate that ATR-inhibition fundamentally rewires cellular signaling networks leading to the prominent activation of different pathways including the ATM-driven double strand break repair.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Petra Beli  

PROVIDER: MSV000080795 | MassIVE | Wed Mar 29 16:38:00 BST 2017

SECONDARY ACCESSION(S): PXD002135

REPOSITORIES: MassIVE

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ATR inhibition rewires cellular signaling networks induced by replication stress.

Wagner Sebastian A SA   Oehler Hannah H   Voigt Andrea A   Dalic Denis D   Freiwald Anja A   Serve Hubert H   Beli Petra P  

Proteomics 20160201 3

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  ...[more]