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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.

Original publication

DOI

10.1093/nar/gks1016

Type

Journal article

Journal

Nucleic Acids Res

Publication Date

07/01/2013

Volume

41

Pages

229 - 241

Keywords

Cell Line, Tumor, Cell Survival, Checkpoint Kinase 1, DNA Damage, DNA Polymerase beta, DNA Replication, HeLa Cells, Humans, Hydroxyurea, Oxidative Stress, Protein Kinases, RNA Interference, Recombinational DNA Repair, S Phase Cell Cycle Checkpoints, Stress, Physiological