ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage

  title={ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage},
  author={Shuhei Matsuoka and Bryan A. Ballif and Agata Smogorzewska and E. Robert McDonald and Kristen E. Hurov and Ji Luo and Corey E. Bakalarski and Zhenming Zhao and Nicole L. Solimini and Yaniv Lerenthal and Yosef Shiloh and Steven P. Gygi and Stephen J. Elledge},
  pages={1160 - 1166}
Cellular responses to DNA damage are mediated by a number of protein kinases, including ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related). The outlines of the signal transduction portion of this pathway are known, but little is known about the physiological scope of the DNA damage response (DDR). We performed a large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR and identified more than 900 regulated… 
A wide-ranging cellular response to UV damage of DNA
The study expanded the number of phosphorylation sites from protein classes known to be involved in the DNA damage response and extended the successful use of the PhosphoScan® proteomic method from phospho-tyrosine to serine/threonine motifs, providing a general blueprint to use the method to study signaling pathways underlying a wide range of diseases.
A Proteome-wide Analysis of Kinase-Substrate Network in the DNA Damage Response*
The DNA damage checkpoint, consisting of an evolutionarily conserved protein kinase cascade, controls the DNA damage response in eukaryotes. Knowledge of the in vivo substrates of the checkpoint
Profiling of UV-induced ATM/ATR signaling pathways
Using immunoaffinity phosphopeptide isolation coupled with mass spectrometry to identify 570 sites phosphorylated in UV-damaged cells, 498 of which are previously undescribed, provide a rich resource for further deciphering ATM/ATR signaling and the pathways mediating the DNA damage response.
A Novel ATM-Dependent Pathway Regulates Protein Phosphatase 1 in Response to DNA Damage
It is reported that IR induces the rapid dissociation of PP1 from its regulatory subunit inhibitor-2 (I-2) and that the process requires ataxia-telangiectasia mutated (ATM), a protein kinase central to DNA damage responses.
ATR as a Therapeutic Target
Ataxia Telangiectasia Mutated and Rad3-related (ATR) is a vital sensor of a variety of DNA lesions and is critical to cell cycle arrest at the S and G2 checkpoints as well as initiation of DNA repair
Profiling DNA damage-induced phosphorylation in budding yeast reveals diverse signaling networks
An unbiased approach to profile DDR-dependent phosphorylation in budding yeast reveals a link between DDR signaling and the metabolic pathways of inositol phosphate and phosphatidyl inositl synthesis, which are required for resistance to DNA damage.
ATM-Dependent and -Independent Dynamics of the Nuclear Phosphoproteome After DNA Damage
An ATM-dependent phosphorylation site on ATM itself was identified that played a role in its retention on damaged chromatin that is in line with the critical importance of genomic stability in maintenance of cellular homeostasis.
Beyond the Trinity of ATM, ATR, and DNA-PK: Multiple Kinases Shape the DNA Damage Response in Concert With RNA Metabolism
Kinase-dependent phosphorylation events on RNAPII, Drosha and Dicer, and 53BP1 that modulate the key steps of the DDR to DSBs and UVR are reviewed, suggesting an intimate link between the DDR and RNA metabolism.


Substrate Specificities and Identification of Putative Substrates of ATM Kinase Family Members*
A general phosphorylation consensus sequence for ATM is determined and putative in vitro targets are identified by using glutathioneS-transferase peptides as substrates by utilizing p53 peptide mutagenesis analysis.
The ATM-mediated DNA-damage response: taking shape.
  • Y. Shiloh
  • Biology
    Trends in biochemical sciences
  • 2006
Involvement of novel autophosphorylation sites in ATM activation
It is concluded that there are at least three functionally important radiation‐induced autophosphorylation events in ATM, including autoph phosphorylation on pS367 and pS1893, which are physiologically important parts of the DNA damage response.
Phosphorylation of FANCD2 on Two Novel Sites Is Required for Mitomycin C Resistance
Two novel DNA damage-inducible phosphorylation sites on FANCD2, threonine 691 and serine 717 are identified and support a role for the FA pathway in the coordination of the S phase of the cell cycle.
Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases.
Four lines of evidence are described that ATM/ATR-dependent (ataxia-telangiectasia-mutated/ATM- and Rad3-related) checkpoint pathways are directly linked to three members of the minichromosome maintenance complex, a platform for multiple DNA damage-dependent regulatory signals that control DNA replication.
Mcm2 Is a Direct Substrate of ATM and ATR during DNA Damage and DNA Replication Checkpoint Responses*
Immunodepletion of both ATM and ATR abrogated the checkpoint response that blocks chromosomal DNA replication in egg extracts containing double-stranded DNA breaks and phosphorylated Mcm2 directly at Ser92 in cell-free kinase assays.
Abraxas and RAP80 Form a BRCA1 Protein Complex Required for the DNA Damage Response
Phosphopeptide affinity proteomic analysis identified a protein, Abraxas, that directly binds the BRCA1 BRCT repeats through a phospho-Ser-X- X-Phe motif, forming a third type of B RCA1 complex.
Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway
It is shown that DSB formation is followed by ATM-dependent chromatin relaxation, which suggests that chromatin Relaxation is a fundamental pathway in the DNA-damage response and identifies its primary mediators.
Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage.
It is shown that the protein kinase, Atm, which belongs to a family of phosphatidylinositol 3-kinases that regulate cell cycle checkpoints and DNA recombination and repair, phosphorylates Smc1 protein after ionizing irradiation.