Defective interplay of activators and repressors with TFIIH in xeroderma pigmentosum

Inherited mutations of the TFIIH helicase subunits xeroderma pigmentosum (X P) B or XPD yield overlapping DNA repair and transcription syndromes. The h igh risk of cancer in these patients is not fully explained by the repair d efect. The transcription defect is subtle and has proven more difficult to evaluate. Here, XPB and XPD mutations are shown to block transcription acti vation by the FUSE Binding Protein (FBP), a regulator of c-myc expression, and repression by the FBP Interacting Repressor (FIR). Through TFIIH, FBP f acilitates transcription until promoter escape, whereas after initiation, F IR uses TFIIH to delay promoter escape. Mutations in TFIIH that impair regu lation by FBP and FIR affect proper regulation of c-myc expression and have implications in the development of malignancy.