biostudies-literatureDannenberg RLStephen and Patricia Benkovic Summer Research Award in ChemistryNational Institutes of HealthNIH HHS9893-9908https://www.ebi.ac.uk/biostudies/studies/S-EPMC9508823biostudies-literatureUnknown50(17)During DNA replication, DNA lesions in lagging strand templates are initially encountered by DNA polymerase δ (pol δ) holoenzymes comprised of pol δ and the PCNA processivity sliding clamp. These encounters are thought to stall replication of an afflicted template before the lesion, activating DNA damage tolerance (DDT) pathways that replicate the lesion and adjacent DNA sequence, allowing pol δ to resume. However, qualitative studies observed that human pol δ can replicate various DNA lesions, albeit with unknown proficiencies, which raises issues regarding the role of DDT in replicating DNA lesions. To address these issues, we re-constituted human lagging strand replication to quantitatively characterize initial encounters of pol δ holoenzymes with DNA lesions. The results indicate pol δNucleic acids researchTracking of progressing human DNA polymerase δ holoenzymes reveals distributions of DNA lesion bypass activities.PMC95088231 R35 GM147238-01Pytko KGHedglin MCardina JADannenberg RLfalseTracking of progressing human DNA polymerase δ holoenzymes reveals distributions of DNA lesion bypass activities.During DNA replication, DNA lesions in lagging strand templates are initially encountered by DNA polymerase δ (pol δ) holoenzymes comprised of pol δ and the PCNA processivity sliding clamp. These encounters are thought to stall replication of an afflicted template before the lesion, activating DNA damage tolerance (DDT) pathways that replicate the lesion and adjacent DNA sequence, allowing pol δ to resume. However, qualitative studies observed that human pol δ can replicate various DNA lesions, albeit with unknown proficiencies, which raises issues regarding the role of DDT in replicating DNA lesions. To address these issues, we re-constituted human lagging strand replication to quantitatively characterize initial encounters of pol δ holoenzymes with DNA lesions. The results indicate pol δ2022-01-01T00:00:00Z2022 Sep2025-04-18T20:56:36.122Z2025-04-07T08:56:05.088ZS-EPMC95088233610777710.1093/nar/gkac745