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

Human DNA polymerase (pol) lambda functions in base excision repair and non-homologous end joining. We have previously shown that DNA pol lambda 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 lambda with the S phase DNA damage response checkpoint. Here, we show that a knockdown of DNA pol lambda, but not of its close homologue DNA pol ?, 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 lambda 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 lambda is required for cell cycle progression and is functionally connected to the S phase DNA damage response machinery in cancer cells.