title: ETAA1 acts at stalled replication forks to maintain genome integrity.
abstract: The ATR checkpoint kinase coordinates cellular responses to DNA replication stress. Budding yeast contain three activators of Mec1 (the ATR orthologue); however, only TOPBP1 is known to activate ATR in vertebrates. We identified ETAA1 as a replication stress response protein in two proteomic screens. ETAA1-deficient cells accumulate double-strand breaks, sister chromatid exchanges, and other hallmarks of genome instability. They are also hypersensitive to replication stress and have increased frequencies of replication fork collapse. ETAA1 contains two RPA-interaction motifs that localize ETAA1 to stalled replication forks. It also interacts with several DNA damage response proteins including the BLM/TOP3α/RMI1/RMI2 and ATR/ATRIP complexes. It binds ATR/ATRIP directly using a motif with sequence similarity to the TOPBP1 ATR-activation domain; and like TOPBP1, ETAA1 acts as a direct ATR activator. ETAA1 functions in parallel to the TOPBP1/RAD9/HUS1/RAD1 pathway to regulate ATR and maintain genome stability. Thus, vertebrate cells contain at least two ATR-activating proteins.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 613 Light Hall, 2215 Garland Avenue, Nashville, Tennessee 37232, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Bass
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 613 Light Hall, 2215 Garland Avenue, Nashville, Tennessee 37232, USA.
authors.forename: Jessica W
authors.initials: JW
authors.lastname: Luzwick
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 613 Light Hall, 2215 Garland Avenue, Nashville, Tennessee 37232, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Kavanaugh
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 613 Light Hall, 2215 Garland Avenue, Nashville, Tennessee 37232, USA.
authors.forename: Clinton
authors.initials: C
authors.lastname: Carroll
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 613 Light Hall, 2215 Garland Avenue, Nashville, Tennessee 37232, USA.
authors.forename: Huzefa
authors.initials: H
authors.lastname: Dungrawala
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 613 Light Hall, 2215 Garland Avenue, Nashville, Tennessee 37232, USA.
authors.forename: Gloria G
authors.initials: GG
authors.lastname: Glick
authors.affiliation: Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldkamp
authors.affiliation: Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Reid
authors.initials: R
authors.lastname: Putney
authors.affiliation: Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Chazin
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 613 Light Hall, 2215 Garland Avenue, Nashville, Tennessee 37232, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cortez
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015894:Genome, Human; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction / Q000235:genetics
chemical_list: C521194:ATRIP protein, human; D048868:Adaptor Proteins, Signal Transducing; D000954:Antigens, Surface; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C508506:ETAA1 protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases