ETAA1 acts at stalled replication forks to maintain genome integrity.

Bass TE, Luzwick JW, Kavanaugh G, Carroll C, Dungrawala H, Glick GG, Feldkamp MD, Putney R, Chazin WJ, Cortez D
Nat Cell Biol. 2016 18 (11): 1185-1195

PMID: 27723720 · PMCID: PMC5245861 · DOI:10.1038/ncb3415

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.

MeSH Terms (15)

Adaptor Proteins, Signal Transducing Antigens, Surface Ataxia Telangiectasia Mutated Proteins Carrier Proteins Cell Cycle Proteins Cell Line DNA-Binding Proteins DNA Damage DNA Replication Genome, Human Genomic Instability Humans Protein-Serine-Threonine Kinases Proteomics Signal Transduction

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