Background: Eukaryotic cells utilize multiple molecular motor proteins to accomplish intracellular transport. Although there exists numerous forms of kinesin for anterograde transport, only a single cytoplasmic form of dynein carries out the functions of retrograde transport. To accomplish its tasks, dynein makes use of multiple subunits and accessory proteins, including heavy chains, light chains, intermediate chains, light intermediate chains, and dynactin to form a motor complex of several megadaltons. Methods and Findings: Numerous dynein heavy chain mutants were isolated previously from a genetic screen in the filamentous fungus Neurospora crassa, with a subset located to the C-terminal region, which were the focal point of this work. To explore the mechanism by which these mutations affect dynein function, both intragenic and extragenic suppressors were identified. A novel extragenic suppressor of dynein mutations was discovered, a gene encoding a putative E3 ubiquitin ligase with homologs present in higher organisms, including humans. Mutation or deletion of the suppressor gene results in restoration of wild type-like growth and in vivo dynein localization for each of the C-terminal dynein heavy chain mutants. Conclusions: Results suggest that mutation of the C-terminal domain of the heavy chain impacts its interaction with dynein intermediate chain. Under this mutated state of dynein heavy chain, a fully functional ubiquitin ligase may act to interfere with proper assembly of the dynein motor.