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.

journal_name

Nat Cell Biol

journal_title

Nature cell biology

authors

Bass TE,Luzwick JW,Kavanaugh G,Carroll C,Dungrawala H,Glick GG,Feldkamp MD,Putney R,Chazin WJ,Cortez D

doi

10.1038/ncb3415

subject

Has Abstract

pub_date

2016-11-01 00:00:00

pages

1185-1195

issue

11

eissn

1465-7392

issn

1476-4679

pii

ncb3415

journal_volume

18

pub_type

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