biostudies-literatureYoon JHNational Institutes of HealthNIH HHSNIGMS NIH HHSRP106934https://www.ebi.ac.uk/biostudies/studies/S-EPMC12408069biostudies-literatureUnknown14Y-family DNA polymerases (Pols) are intrinsically highly error-prone; yet they conduct predominantly error-free translesion synthesis (TLS) in normal human cells. In response to DNA damage, Y-family Pols assemble and function together with WRN, WRNIP1, and Rev1 in TLS. Among these proteins, WRN possesses a 3'→5' exonuclease activity and an ATPase/3'→5' DNA helicase activity, and WRNIP1 has a DNA-dependent ATPase activity. In a previous study, we identified a role of WRN 3'→5' exonuclease activity in the high in vivo fidelity of TLS by Y-family Pols. Here we provide evidence for a crucial role of WRN and WRNIP1 ATPase activities in raising the fidelity of TLS by these Pols. Defects in WRN and WRNIP1 ATPase activities cause a diversity of nucleotide (nt) misincorporations opposite DNA lesioneLifeWRN and WRNIP1 ATPases impose high fidelity on translesion synthesis by Y-family DNA polymerases.PMC12408069R35 GM148364Sellamuthu KPrakash SYoon JHPrakash LfalseWRN and WRNIP1 ATPases impose high fidelity on translesion synthesis by Y-family DNA polymerases.Y-family DNA polymerases (Pols) are intrinsically highly error-prone; yet they conduct predominantly error-free translesion synthesis (TLS) in normal human cells. In response to DNA damage, Y-family Pols assemble and function together with WRN, WRNIP1, and Rev1 in TLS. Among these proteins, WRN possesses a 3'→5' exonuclease activity and an ATPase/3'→5' DNA helicase activity, and WRNIP1 has a DNA-dependent ATPase activity. In a previous study, we identified a role of WRN 3'→5' exonuclease activity in the high in vivo fidelity of TLS by Y-family Pols. Here we provide evidence for a crucial role of WRN and WRNIP1 ATPase activities in raising the fidelity of TLS by these Pols. Defects in WRN and WRNIP1 ATPase activities cause a diversity of nucleotide (nt) misincorporations opposite DNA lesion2025-01-01T00:00:00Z2025 Sep2026-07-15T12:42:31.117Z2026-07-04T03:16:08.154ZS-EPMC124080694090014810.7554/eLife.106934