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

J Cell Biol. 2019 Sep 2;218(9):2865-2875. doi: 10.1083/jcb.201902085. Epub 2019 Jul 31.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Survival
  • Checkpoint Kinase 1 / genetics
  • Checkpoint Kinase 1 / metabolism*
  • Enzyme Stability / genetics
  • Genomic Instability*
  • HeLa Cells
  • Humans
  • Proteolysis*
  • S Phase Cell Cycle Checkpoints*
  • Ubiquitination*

Substances

  • Antigens, Surface
  • ETAA1 protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1