ETAA1 Acts at Stalled Replication Forks to Maintain Genome Integrity

Authors

Thomas E. Bass, Vanderbilt University School of Medicine
Jessica W. Luzwick, Vanderbilt University School of Medicine
Gina Kavanaugh, Vanderbilt University School of Medicine
Clinton Carroll, Vanderbilt University School of Medicine
Huzefa Dungrawala, Vanderbilt University School of MedicineFollow
Gloria G. Glick, Vanderbilt University School of Medicine
Michael D. Feldkamp, Vanderbilt University
Reid Putney, Vanderbilt University
Walter J. Chazin, Vanderbilt University
David Cortez, Vanderbilt University School of Medicine

Document Type

Article

Publication Date

2016

Keywords

DNA damage and repair, DNA damage response, Double-strand DNA breaks

Digital Object Identifier (DOI)

https://doi.org/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. Bass et al. and Haahr et al. identify ETAA1 as a critical replication stress response factor that interacts with DNA damage response proteins and activates ATR to maintain genomic stability.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

Nature Cell Biology, v. 18, p. 1185-1195

Scholar Commons Citation

Bass, Thomas E.; Luzwick, Jessica W.; Kavanaugh, Gina; Carroll, Clinton; Dungrawala, Huzefa; Glick, Gloria G.; Feldkamp, Michael D.; Putney, Reid; Chazin, Walter J.; and Cortez, David, "ETAA1 Acts at Stalled Replication Forks to Maintain Genome Integrity" (2016). Molecular Biosciences Faculty Publications. 103.
https://digitalcommons.usf.edu/bcm_facpub/103