DNA repair is a pivotal mechanism in maintaining genetic integrity and cell fate determination. As unrepaired DNA lesions inhibit transcription, UV-induced damage to transcribed DNA is repaired preferentially versus non-transcribed DNA through transcription-coupled nucleotide excision repair (TCR). Previously, we reported that TCR-related genes serve as transcription elongation factors, and defects of the genes drastically increase mutagenesis. Extensive studies on DNA damage repair have provided key information about the pathways controlling replication across DNA lesions. However, knowledge of the mechanisms dealing with stalled DNA transcription is insufficient. In this study, we demonstrated the requirement for SPT4 in cell growth along with its role in mutagenesis in both the presence and absence of DNA damage. SPT4 appeared to promote transcription elongation across DNA lesions, thereby increasing the cell survival rate in exchange for increased mutagenesis. Further, our results explain the decrease in mutant Huntingtin protein in neuronal cells upon inhibition of Supt4, the mammalian ortholog of yeast Spt4p.