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Basal CHK1 activity safeguards its stability to maintain intrinsic S-phase checkpoint functions


Michelena, Jone; Gatti, Marco; Teloni, Federico; Imhof, Ralph; Altmeyer, Matthias (2019). Basal CHK1 activity safeguards its stability to maintain intrinsic S-phase checkpoint functions. Journal of Cell Biology, 218(9):2865-2875.

Abstract

The DNA replication machinery frequently encounters impediments that slow replication fork progression and threaten timely and error-free replication. The CHK1 protein kinase is essential to deal with replication stress (RS) and ensure genome integrity and cell survival, yet how basal levels and activity of CHK1 are maintained under physiological, unstressed conditions is not well understood. Here, we reveal that CHK1 stability is controlled by its steady-state activity during unchallenged cell proliferation. This autoactivatory mechanism, which depends on ATR and its coactivator ETAA1 and is tightly associated with CHK1 autophosphorylation at S296, counters CHK1 ubiquitylation and proteasomal degradation, thereby preventing attenuation of S-phase checkpoint functions and a compromised capacity to respond to RS. Based on these findings, we propose that steady-state CHK1 activity safeguards its stability to maintain intrinsic checkpoint functions and ensure genome integrity and cell survival.

Abstract

The DNA replication machinery frequently encounters impediments that slow replication fork progression and threaten timely and error-free replication. The CHK1 protein kinase is essential to deal with replication stress (RS) and ensure genome integrity and cell survival, yet how basal levels and activity of CHK1 are maintained under physiological, unstressed conditions is not well understood. Here, we reveal that CHK1 stability is controlled by its steady-state activity during unchallenged cell proliferation. This autoactivatory mechanism, which depends on ATR and its coactivator ETAA1 and is tightly associated with CHK1 autophosphorylation at S296, counters CHK1 ubiquitylation and proteasomal degradation, thereby preventing attenuation of S-phase checkpoint functions and a compromised capacity to respond to RS. Based on these findings, we propose that steady-state CHK1 activity safeguards its stability to maintain intrinsic checkpoint functions and ensure genome integrity and cell survival.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Cell Biology
Uncontrolled Keywords:Cell Biology
Language:English
Date:2 September 2019
Deposited On:26 Aug 2019 16:42
Last Modified:29 Jul 2020 11:10
Publisher:Rockefeller University Press
ISSN:0021-9525
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1083/jcb.201902085
PubMed ID:31366665
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P3_179057
  • : Project TitleUncovering concealed regulators and unexpected pathway connections guarding against genome instability
  • : FunderSNSF
  • : Grant IDPP00P3_150690
  • : Project TitleUncovering concealed regulators and unexpected pathway connections guarding against genome instability

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