Transcription is coupled with DNA repair, ensuring the continuity of Pol II progression. DNA lesions can potentially lead to problems in development, cell growth and survival. Proteins first identified as components of transcription or DNA repair machineries may be involved in both processes, like TFIIH. Nucleotide-excision DNA repair (NER) is a major DNA repair pathway that removes DNA lesions such as cyclobutane pyrimidine dimers (CPD) arising upon UV irradiation. Global genome repair pathway removes DNA lesions in the genome overall, and transcription-coupled repair removes DNA lesions that interfere with the progression of Pol II through actively-transcribed genes. While the NER reaction and the components required for efficient DNA lesion recognition and repair are fairly well understood in vitro, many questions on the active coupling of DNA repair with transcription remain still unanswered in vivo, notably on the genomic scale.

Our two-hybrid screening with Mediator subunits permits us to uncover a number of interactions between Mediator and other components of the nucleus (unpublished data). One particularly interesting interaction that we have identified is the contact between one of the Mediator subunits and a DNA repair protein. We uncovered a new role of Mediator by connecting transcription and DNA repair via this direct contact with Rad2 endonuclease, the yeast homolog of human XPG protein. Mutations in human XPG gene give rise to a xeroderma pigmentosum (XP) associated with Cockayne syndrome (CS) disease. Our results indicated that Mediator is involved in transcription-coupled DNA repair by facilitating Rad2 recruitment to transcribed genes. We propose that in addition to its fundamental coactivator role, Mediator acts in essential nuclear processes beyond transcription.