The UNG2 Arg88Cys variant abrogates RPA-mediated recruitment of UNG2 to single-stranded DNA

► The human R88C variant of UNG2 is expressed from the variant allele as a fully active enzyme. ► The R88C substitution resides in the RPA-binding motif of UNG2 and abolishes binding to RPA. ► In the absence of PCNA-binding, functional RPA-binding is essential to recruit UNG2 to stalled replication forks. ► Binding to PCNA versus RPA may constitute a functional switch for UNG2 during cellular stress.