2. Academic Validation
  3. ETAA1 acts at stalled replication forks to maintain genome integrity

ETAA1 acts at stalled replication forks to maintain genome integrity

  • Nat Cell Biol. 2016 Nov;18(11):1185-1195. doi: 10.1038/ncb3415.
Thomas E Bass 1,  Jessica W Luzwick 1,  Gina Kavanaugh 1,  Clinton Carroll 1,  Huzefa Dungrawala 1,  Gloria G Glick 1,  Michael D Feldkamp 2,  Reid Putney 2,  Walter J Chazin 2,  David Cortez 1
Affiliations

Affiliations

  • 1 Department of Biochemistry, Vanderbilt University School of Medicine, 613 Light Hall, 2215 Garland Avenue, Nashville, Tennessee 37232, USA.
  • 2 Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.
PMID: 27723720 DOI: 10.1038/ncb3415
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.

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