We sought to evaluate the contribution of muSOX-induced mRNA turnover towards the gammaherpesvirus lifecycle through the generation of a muSOX mutant lacking mRNA turnover activity but retaining the conserved DNase function. We engineered mutations in the sites necessary for host shutoff activity in muSOX homologs from other gammaherpesviruses (EBV BGLF5 [25] and KSHV SOX [26] ), as well as in several sites selectively conserved amongst these homologs that lay outside the putative DNase domains [27] . However, none of the mutants generated had the desired single-function phenotype (Table S1) .