Lineage-specific control of TFIIH by MITF determines transcriptional homeostasis and DNA repair
Nucleotide excision repair (NER) and transcriptional homeostasis are intricately intertwined, vitally important processes which maintain genomic stability in eukaryotes. The importance of the functional interplay of DNA repair and transcription is reflected by transcription deficiency disorders of childhood such as Cockayne syndrome and trichothiodystrophy which result in severe neurological developmental deficits, intellectual disability, seizures and reduced life expectancy. Their underlying pathology is a genetic defect of transcription-coupled DNA repair. Researchers at the Children's Cancer Center Hamburg now show that the transcriptional master regulators Microphthalmia and c-MYC operate at the interface of DNA repair and transcription in the melanocytic lineage by transactivation of GTF2H1 and CDK7 as core components of the TFIIH-CAK initiation complex. The transactivation of TFIIH-kinase (CDK7) by sequence-specific transcription factors feeds into transcriptional circuitries driven by super-enhancers or other oncogenic mechanisms, which constitute a vulnerability potentially amenable to a transcription-targeted treatment approach to hard-to-treat cancers such as N-MYC dependent neuroblastoma and medulloblastoma of childhood.
Lineage-specific control of TFIIH by MITF determines transcriptional homeostasis and DNA repair.
Seoane M, Buhs S, Iglesias P, Strauss J, Puller AC, Müller J, Gerull H, Feldhaus S, Alawi M, Brandner JM, Eggert D, Du J, Thomale J, Wild PJ, Zimmermann M, Sternsdorf T, Schumacher U, Nollau P, Fisher DE, Horstmann MA. Oncogene. 2019 Jan 16. doi: 10.1038/s41388-018-0661-x.