Multiple ubiquitin ligases with nuclear substrates promote regulated protein degradation and turnover of protein quality control (PQC) substrates. We hypothesized that two ubiquitin ligases with nuclear substrates – the anaphase-promoting complex/cyclosome with the Cdh1p substrate recognition factor (APC/C Cdh1p ) and the Slx5p/Slx8p SUMO-targeted ubiquitin ligase – contribute to PQC. We predicted yeast lacking subunits of these enzymes would exhibit compromised growth in the presence of hygromycin B, which reduces translational fidelity. We observed that loss of Cdh1p, Slx5p, or Slx8p sensitizes yeast to hygromycin B to a similar extent as loss of two ubiquitin ligases with characterized roles in nuclear PQC and hygromycin B resistance. In addition to their well-characterized function in regulated protein degradation, our results are consistent with prominent roles for both APC/C Cdh1p and Slx5p/Slx8p in PQC.