ETAA1 acts at stalled replication forks to maintain genome integrity

Nat Cell Biol. 2016 Nov;18(11):1185-1195. doi: 10.1038/ncb3415. Epub 2016 Oct 10.

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.

MeSH terms

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

Substances

  • ATRIP protein, human
  • Adaptor Proteins, Signal Transducing
  • Antigens, Surface
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • ETAA1 protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases