Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription

Curr Biol. 2013 Sep 9;23(17):1629-37. doi: 10.1016/j.cub.2013.06.063. Epub 2013 Aug 15.

Abstract

Background: In eukaryotic cells, detection of replication stress results in the activation of the DNA replication checkpoint, a signaling cascade whose central players are the kinases ATR and Chk1. The checkpoint response prevents the accumulation of DNA damage and ensures cell viability by delaying progression into mitosis. However, the role and mechanism of the replication checkpoint transcriptional response in human cells, which is p53 independent, is largely unknown.

Results: We show that, in response to DNA replication stress, the regular E2F-dependent cell-cycle transcriptional program is maintained at high levels, and we establish the mechanisms governing such transcriptional upregulation. E2F6, a repressor of E2F-dependent G1/S transcription, replaces the activating E2Fs at promoters to repress transcription in cells progressing into S phase in unperturbed conditions. After replication stress, the checkpoint kinase Chk1 phosphorylates E2F6, leading to its dissociation from promoters. This promotes E2F-dependent transcription, which mediates cell survival by preventing DNA damage and cell death.

Conclusions: This work reveals, for the first time, that the regular cell-cycle transcriptional program is part of the DNA replication checkpoint response in human cells and establishes the molecular mechanism involved. We show that maintaining high levels of G1/S cell-cycle transcription in response to replication stress contributes to two key functions of the DNA replication checkpoint response, namely, preventing genomic instability and cell death. Given the critical role of replication stress in oncogene transformation, a detailed understanding of the molecular mechanisms involved in the checkpoint response will contribute to a better insight into cancer development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / genetics*
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • DNA Damage
  • DNA Replication*
  • E2F6 Transcription Factor / physiology*
  • Humans
  • Promoter Regions, Genetic
  • Protein Kinases / physiology*
  • Transcription, Genetic / physiology*

Substances

  • E2F6 Transcription Factor
  • E2F6 protein, human
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1