Noncanonical Role of the 9-1-1 Clamp in the Error-Free DNA Damage Tolerance Pathway

SummaryDamaged DNA is an obstacle during DNA replication and a cause of genome instability and cancer. To bypass this problem, eukaryotes activate DNA damage tolerance (DDT) pathways that involve ubiquitylation of the DNA polymerase clamp proliferating cell nuclear antigen (PCNA). Monoubiquitylation of PCNA mediates an error-prone pathway by recruiting translesion polymerases, whereas polyubiquitylation activates an error-free pathway that utilizes undamaged sister chromatids as templates. The error-free pathway involves recombination-related mechanisms; however, the factors that act along with polyubiquitylated PCNA remain largely unknown. Here we report that the PCNA-related 9-1-1 complex, which is typically linked to checkpoint signaling, participates together with Exo1 nuclease in error-free DDT. Notably, 9-1-1 promotes template switching in a manner that is distinct from its canonical checkpoint functions and uncoupled from the replication fork. Our findings thus reveal unexpected cooperation in the error-free pathway between the two related clamps and indicate that 9-1-1 plays a broader role in the DNA damage response than previously assumed.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (309 K)Download as PowerPoint slideHighlights► 9-1-1 and Exo1 are components of the error-free RAD6 pathway ► 9-1-1 promotes postreplicative template switching ► Polyubiquitylated PCNA and 9-1-1 cooperate in the error-free RAD6 pathway ► 9-1-1’s role in the error-free RAD6 pathway is uncoupled from checkpoint functions