Mol Cell Toxicol (2013) 9:37-43 DOI 10.1007/s13273-013-0006-3 Abstract DNA repair is a pivotal mechanism in maintaining genetic integrity and cell fate determina- tion. 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 transcrip- tion elongation across DNA lesions, thereby increasing the cell survival rate in exchange for increased mutage- nesis. Further, our results explain the decrease in mutant Huntingtin protein in neuronal cells upon inhibition of Supt4, the mammalian ortholog of yeast Spt4p. Keywords SPT4, RAD2, Transcription elongation, Mutagenesis, DNA repair Cellular DNA is continuously damaged by various endogenous and environmental factors, including ultra violet light (UV) and chemical pollutants. To effective- ly deal with DNA damage and maintain genetic inte- grity, cell cycle checkpoint systems modulate various cellular mechanisms such as DNA replication and transcription 1-5 . Both replication and transcription polymerases may become stalled upon encountering DNA damages. However, if the stall is prolonged, replication is bypassed, or cell death could be initiated in order to remove damaged cells. Extensive studies on DNA damage repair have provided key information about the pathways controlling replication across DNA lesions. However, knowledge of the mechanisms deal- ing with stalled DNA transcription is insufficient. Damaged DNA is repaired by several specialized damaged DNA repair systems including nucleotide excision repair (NER), base excision repair (BER), mismatch repair, and recombination repair 5-7 . Mutation of XPG, a homolog of yeast RAD2 gene that encodes NER endonuclease, induces inherited genetic disorders, xeroderma pigmentosum and Cockayne syndrome in humans 8 . RAD2 also functions in transcription elonga- tion 9 , and stalling of transcription at DNA lesions is thought to be highly mutagenic 10 . Previously, we showed that the 6-azauracil (6AU) sensitivity of rad2Δ mutant can be complemented by deletion of puf4, and many genes are differentially expressed in rad2Δ and rad2Δpuf4Δ mutants 11 . Among these differentially expressed genes, SPT4 is involved in Polymerase II (RNAP II) transcription elongation through reduction of RNAPII dissociation from the DNA template 12-14 . SPT4 is also known to be involved in RAD26-dependent TCR 15,16 . SPT4 expression, in the presence of 6AU, is reduced in the rad2Δ mutant compared to wild-type, whereas its expression is in- creased in both puf4Δ and rad2Δpuf4Δ mutants. These results showed that SPT4 expression is indeed modu- lated by PUF4 and RAD2 11,17 . ORIGINAL PAPER SPT4 increases UV-induced mutagenesis in yeast through impaired nucleotide excision repair Mi-Sun Kang 1,2, * , Sung-Lim Yu 3, * , Ho-Yeol Kim 1,2 , Hyun-Sook Lim 1,2 & Sung-Keun Lee 1,2 Received: 2 December 2012 / Accepted: 26 December 2012 �The Korean Society of Toxicogenomics and Toxicoproteomics and Springer 2013 1 Department of Pharmacology, Inha Research Institute for Medical Sciences and 2 Center for Advanced Medical Education, 3 Inha Research Institute for Medical Sciences, Inha University College of Medicine by BK-21 Project, Incheon 400-712, Korea *These authors contributed equally to this work Correspondence and requests for materials should be addressed to S.-K. Lee ( sungkeun@inha.ac.kr)