Impeding the formation of Transcription Initiation complex

RNA synthesis is the result of a cascade of chronologically orchestrated events that requires several hundreds of proteins including RNA polymerase II, the general transcription factors, mediator, co‐activators, co‐repressors and chromatin remodelers are assembled around the promoter. Among these proteins necessary to initiate RNA synthesis, we recently identified the Nucleotide‐Excision‐Repair (NER) factors demonstrating their dual role in transcription and DNA repair. Mediator occupies a key role in protein coding genes expression in mediating the contacts between gene specific factors and the basal transcription machinery. Mutations in one of these factors results in rare genetic disorders: Xeroderma Pigmentosum (XP), Trichothiodystrophy (TTD), Cockayne Syndrome (CS), for TFIIH and NER factors; non‐syndromic mental retardation, Charcot‐Marie Tooth, Opitz‐Kaveggia … for Mediator. We show how each of the mutations in either NER factors or Mediator subunits specifically disturbs the protein/protein interactions network required for the accurate formation of the transcription complex at the promoter of activated genes. The NER proteins seem to be necessary at the promoter of activated genes in order to achieve an optimal 3D loop structure that requires DNA demethylation, formation of DNA cuts as well as histone posttranslational modifications. We also show how the Mediator mutations cause distinct expression of Immediate Early Genes (IEG) with as a consequence disruption of later genes expression. Our study shed light on the molecular mechanism underlying gene expression regulation at the transcription initiation level explaining at least partially some of the clinical features of the above‐mentioned genetic disorders.