TTDA: big impact of a small protein

Nucleotide excision repair (NER) is a highly versatile DNA repair process which is able to remove a broad spectrum of structurally unrelated DNA helix-destabilizing lesions. The multi-subunit transcription/repair factor IIH (TFIIH) is an important decision maker in NER, by opening the DNA double helix after the initial damage recognition and subsequently verifying the lesion. Inherited mutations in TFIIH subunits are associated with NER-deficiency and a perplexing clinical heterogeneity, ranging from cancer-prone Xeroderma Pigmentosum to the progeroid diseases Cockayne Syndrome and Trichothio-dystrophy (TTD). Three different TFIIH coding genes are implicated in TTD: XPD, XPB and TTDA. The latter gene encodes for a small (71 amino-acid) subunit and appeared important for the stabilization of the entire TFIIH complex. Based on analyzing TTD group A patient derived cells it was initially thought that TTDA has only a NER-stimulating role. In this review we summarize recent data showing that full disruption of TTDA expression in a knock-out mouse-model completely inactivates NER. Surprisingly, next to being essential for NER, TTDA appeared to be required also for embryonic development, indicative for the big impact this small protein has on basal biological processes. (C) 2014 Elsevier Inc. All rights reserved.