A novel role for ATR/Rad3 in G1 phase

Sci Rep. 2018 May 2;8(1):6880. doi: 10.1038/s41598-018-25238-6.


Checkpoint kinases are important in cellular surveillance pathways that help cells to cope with DNA damage and protect their genomes. In cycling cells, DNA replication is one of the most sensitive processes and therefore all organisms carefully regulate replication initiation and progression. The checkpoint kinase ATR plays important roles both in response to DNA damage and replication stress, and ATR inhibitors are currently in clinical trials for cancer treatment. Therefore, it is important to understand the roles of ATR in detail. Here we show that the fission yeast homologue Rad3 and the human ATR regulate events also in G1 phase in an unperturbed cell cycle. Rad3Δ mutants or human cells exposed to ATR inhibitor in G1 enter S phase prematurely, which results in increased DNA damage. Furthermore, ATR inhibition in a single G1 reduces clonogenic survival, demonstrating that long-term effects of ATR inhibition during G1 are deleterious for the cell. Interestingly, ATR inhibition through G1 and S phase reduces survival in an additive manner, strongly arguing that different functions of ATR are targeted in the different cell-cycle phases. We propose that potential effects of ATR inhibitors in G1 should be considered when designing future treatment protocols with such inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Checkpoint Kinase 2 / antagonists & inhibitors
  • Checkpoint Kinase 2 / genetics
  • Checkpoint Kinase 2 / metabolism*
  • G1 Phase*
  • Humans
  • Protein Kinase Inhibitors / pharmacology
  • S Phase
  • Schizosaccharomyces
  • Schizosaccharomyces pombe Proteins / antagonists & inhibitors
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism*


  • Protein Kinase Inhibitors
  • Schizosaccharomyces pombe Proteins
  • Checkpoint Kinase 2
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • rad3 protein, S pombe