Transcription-Coupled Repair of DNA Interstrand Crosslinks by UVSSA

DNA interstrand crosslinks (ICLs) are covalent bonds between opposing strands of the DNA helix which prevent DNA melting and subsequent DNA replication or RNA transcription. Here, we show that UV Stimulated Scaffold Protein A (UVSSA) participates in transcription-coupled repair of ICLs. UVSSA encodes a protein that regulates the activity of RNA polymerase II (Pol II) to facilitate the repair of UV lesions and to relieve transcription stress resulting from MYC activation. We show that UVSSA knockout sensitizes cells to ICL-inducing drugs, that UVSSA is specifically required for transcription-coupled repair of a single ICL in a fluorescence-based reporter assay, and that transcription-coupled repair of ICLs is defective in UVSSA(−/−) cells. UVSSA localizes to chromatin upon ICL damage, and interacts with transcribing Pol II, CSA, CSB, and TFIIH. The UVSSA-TFIIH interaction facilitates ICL repair. Finally, UVSSA expression positively correlates with ICL chemotherapy resistance in cancer cell lines. Our data strongly suggest that transcription-coupled ICL repair (TCICR) is a bona fide ICL repair mechanism that contributes to crosslinker drug resistance independently of replication-coupled ICL repair.