Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Immune regulation by fibroblasts in tissue injury depends on uPARAP-mediated uptake of collectins

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Comparison of two different culture conditions for derivation of early hiPSC

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Human embryonic stem cells in culture possess primary cilia with hedgehog signaling machinery

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Intracellular collagen degradation mediated by uPARAP/Endo180 is a major pathway of extracellular matrix turnover during malignancy

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Response to Olaparib in a PALB2 Germline Mutated Prostate Cancer and Genetic Events Associated with Resistance

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. The landscape of genomic alterations across childhood cancers

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Divya Achuthankutty
  • Roshan Singh Thakur
  • Peter Haahr
  • Saskia Hoffmann
  • Alexandros P Drainas
  • Anna H Bizard
  • Joachim Weischenfeldt
  • Ian D Hickson
  • Niels Mailand
View graph of relations

The ATR kinase is a master regulator of the cellular response to DNA replication stress. Activation of ATR relies on dual pathways involving the TopBP1 and ETAA1 proteins, both of which harbor ATR-activating domains (AADs). However, the exact contribution of the recently discovered ETAA1 pathway to ATR signaling in different contexts remains poorly understood. Here, using an unbiased CRISPR-Cas9-based genome-scale screen, we show that the ATR-stimulating function of ETAA1 becomes indispensable for cell fitness and chromosome stability when the fidelity of DNA replication is compromised. We demonstrate that the ATR-activating potential of ETAA1 is controlled by cell cycle- and replication stress-dependent phosphorylation of highly conserved residues within its AAD, and that the stimulatory impact of these modifications is required for the ability of ETAA1 to prevent mitotic chromosome abnormalities following replicative stress. Our findings suggest an important role of ETAA1 in protecting against genome instability arising from incompletely duplicated DNA via regulatory control of its ATR-stimulating potential.

Original languageEnglish
JournalJournal of Cell Biology
ISSN0021-9525
DOIs
Publication statusPublished - 15 Oct 2019

ID: 58182163