Mdm2 is a RING finger-dependent ubiquitin protein ligase that ubiquitinates both itself and p53. The study shows that Mdm2's E3 activity is dependent on its RING finger domain, which coordinates zinc. Mutation of zinc-coordinating residues in the RING finger abrogates this activity, while addition of zinc restores it. Mdm2 also mediates its own ubiquitination and proteasomal degradation, which requires no eukaryotic proteins other than E1 and E2. The RING finger of Mdm2 is essential for its ability to ubiquitinate p53 and itself. Replacing the RING finger of Mdm2 with that of another protein, such as Praja1, allows for ubiquitination and proteasomal degradation of Mdm2, but not of p53, suggesting that the RING finger may have specificity in recognizing substrates. The study also shows that the degradation of p53 and Mdm2 in cells requires additional zinc-coordinating residues beyond those required for intrinsic activity in vitro. The RING finger of Mdm2 is conserved and contains eight cysteines and histidines that coordinate zinc. Mutation of these residues affects the ability of Mdm2 to ubiquitinate p53. The study also demonstrates that the RING finger of Mdm2 is required for its ability to target p53 for degradation in cells. The findings suggest that the RING finger of Mdm2 is essential for its function as an E3 ubiquitin ligase. The study also highlights the importance of the RING finger in the regulation of p53 and Mdm2, and its potential as a target for therapeutic intervention in cancer.Mdm2 is a RING finger-dependent ubiquitin protein ligase that ubiquitinates both itself and p53. The study shows that Mdm2's E3 activity is dependent on its RING finger domain, which coordinates zinc. Mutation of zinc-coordinating residues in the RING finger abrogates this activity, while addition of zinc restores it. Mdm2 also mediates its own ubiquitination and proteasomal degradation, which requires no eukaryotic proteins other than E1 and E2. The RING finger of Mdm2 is essential for its ability to ubiquitinate p53 and itself. Replacing the RING finger of Mdm2 with that of another protein, such as Praja1, allows for ubiquitination and proteasomal degradation of Mdm2, but not of p53, suggesting that the RING finger may have specificity in recognizing substrates. The study also shows that the degradation of p53 and Mdm2 in cells requires additional zinc-coordinating residues beyond those required for intrinsic activity in vitro. The RING finger of Mdm2 is conserved and contains eight cysteines and histidines that coordinate zinc. Mutation of these residues affects the ability of Mdm2 to ubiquitinate p53. The study also demonstrates that the RING finger of Mdm2 is required for its ability to target p53 for degradation in cells. The findings suggest that the RING finger of Mdm2 is essential for its function as an E3 ubiquitin ligase. The study also highlights the importance of the RING finger in the regulation of p53 and Mdm2, and its potential as a target for therapeutic intervention in cancer.