Silencing of human DNA polymerase λ causes replication stress and is synthetically lethal with an impaired S phase checkpoint

Nucleic Acids Res. 2013 Jan 7;41(1):229-41. doi: 10.1093/nar/gks1016. Epub 2012 Oct 30.


Human DNA polymerase (pol) λ functions in base excision repair and non-homologous end joining. We have previously shown that DNA pol λ is involved in accurate bypass of the two frequent oxidative lesions, 7,8-dihydro-8-oxoguanine and 1,2-dihydro-2-oxoadenine during the S phase. However, nothing is known so far about the relationship of DNA pol λ with the S phase DNA damage response checkpoint. Here, we show that a knockdown of DNA pol λ, but not of its close homologue DNA pol β, results in replication fork stress and activates the S phase checkpoint, slowing S phase progression in different human cancer cell lines. We furthermore show that DNA pol λ protects cells from oxidative DNA damage and also functions in rescuing stalled replication forks. Its absence becomes lethal for a cell when a functional checkpoint is missing, suggesting a DNA synthesis deficiency. Our results provide the first evidence, to our knowledge, that DNA pol λ is required for cell cycle progression and is functionally connected to the S phase DNA damage response machinery in cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Survival
  • Checkpoint Kinase 1
  • DNA Damage
  • DNA Polymerase beta / antagonists & inhibitors
  • DNA Polymerase beta / metabolism
  • DNA Polymerase beta / physiology*
  • DNA Replication*
  • HeLa Cells
  • Humans
  • Hydroxyurea / pharmacology
  • Oxidative Stress
  • Protein Kinases / metabolism
  • RNA Interference
  • Recombinational DNA Repair
  • S Phase Cell Cycle Checkpoints*
  • Stress, Physiological / genetics


  • Protein Kinases
  • Checkpoint Kinase 1
  • DNA polymerase beta2
  • DNA Polymerase beta
  • Hydroxyurea