WRN 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 lesions by Y-family Pols, implicating an unprecedented role of these activities in restraining nt misincorporations, which they could accomplish by tightening the active site of the TLS Pol. Altogether, the combined actions of WRN and WRNIP1 ATPases in preventing nt misincorporations and of WRN exonuclease in removing misinserted nts confer such an enormous rise in the fidelity of Y-family Pols that they perform error-free TLS – essential for genome stability and cellular homeostasis.