title: Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription.
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.
authors: MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
authors: Cosetta
authors: C
authors: Bertoli
authors: Steffi
authors: S
authors: Klier
authors: Clare
authors: C
authors: McGowan
authors: Curt
authors: C
authors: Wittenberg
authors: Robertus A M
authors: RA
authors: de Bruin
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004261:DNA Replication; D050701:E2F6 Transcription Factor / Q000502:physiology*; D006801:Humans; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D050701:E2F6 Transcription Factor; C491744:E2F6 protein, human; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
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