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

The Journal of Cell Biology
Jone MichelenaMatthias Altmeyer

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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Citations

Nov 13, 2019·The Journal of Cell Biology·Bennie Lemmens, Arne Lindqvist
Jan 28, 2021·Molecular Cell·Camilla FrattiniAngelos Constantinou
Dec 7, 2020·Trends in Biochemical Sciences·Andreas Panagopoulos, Matthias Altmeyer
Dec 15, 2020·Current Opinion in Cell Biology·Aleksandra Lezaja, Matthias Altmeyer
May 8, 2021·Molecular Cell·Nishita ParnandiDipanjan Chowdhury
Jun 24, 2021·Nature Communications·Aleksandra LezajaMatthias Altmeyer
Sep 2, 2021·Nucleic Acids Research·Diletta CiardoKathrin Marheineke

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Methods Mentioned

BETA
immunoprecipitation
transfection
transfections
PCR

Software Mentioned

Fiji
Olympus ScanR Image Analysis
ImageJ
GraphPad Prism
Spotfire
QIBC

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