CURLY LEAF (CLF) encodes the methyl-transferase sub-unit of the Polycomb Repressor Complex 2 (PRC2), which regulates the expression of target genes through H3K27 tri-methylation. We isolated a new CLF mutant allele (clf-78) using a genetic screening designed to identify micro RNAs (miRNA) deficient mutants. CLF mutant plants showed impaired miRNA activity caused by increased AGO1 ubiquitination and enhanced degradation in specific tissues. Such CLF-mediated AGO1 regulation was evidenced when plants were exposed to UV radiation, causing increased susceptibility of clf mutants to some UV-induced responses. Furthermore, we showed that CLF directly regulates FBW2, which in turn triggers AGO1 degradation in the mutants. Interestingly, AGO1 bound to a target appeared particularly prone to degradation in the mutant plants, a process that is exacerbated when the complex bound a non-cleavable target. Thus, a prolonged AGO1-target interaction seems to favor AGO1 degradation, suggesting that non-cleavable miRNA targets may overcome translation inhibition by modulating AGO1 stability in plants.