MITF controls the interface of nucleotide excision repair and transcription through direct regulation of GTF2H1

• Published in: Klinische Pädiatrie
• Main Authors: Seoane, M, Strauss, J, Puller, AC, Noshiravani, M, Feldhaus, S, Alawi, M, Kaul, MG, Brandner, JM, Du, J, Thomale, J, Wild, PJ, Zimmermann, M, Sternsdorf, T, Nollau, P, Schumacher, U, Fisher, DE, Horstmann, MA
• Format: Conference Proceeding
• Language: English
• Published: 27.07.2015
• ISSN: 0300-8630; 1439-3824
• DOI: 10.1055/s-0035-1550259

Survival, proliferation and differentiation of the melanocytic lineage are determined by the Microphthalmia-associated transcription factor (MITF). MITF's pivotal role in lineage survival is underscored by the observations that its mutation entails a substantial loss of melanocyte viability and its expression is largely maintained upon malignant transformation. Even though it is still incompletely understood how MITF is linked to melanomagenesis. We observed that the lineage-survival oncogene MITF controls the interface of nucleotide excision repair (NER) and transcription, an essential instrument to maintain genomic stability in eukaryotes, through transactivation of the general transcription factor 2H1 ( GTF2H1 ), a TFIIH core element Our results show that the NER/TFIIH complex is controlled by MITF in the presence and absence of UVR mediated genotoxic attack resulting in nucleotide repair deficiency and breakdown of global transcription upon MITF depletion. Importantly, in primary human melanoma the TFIIH subunit GTF2H1, which is involved in NER and RNA transcription, is linked to MITF abundance and prognostic melanoma stage. Moreover, RNA-interference mediated repression of GTF2H1 led to a significant reduction in tumor formation in a melanoma xenograft model. Collectively, these results describe an unanticipated role of MITF in the regulation of intimately linked NER and transcription machineries in the melanocytic lineage, which is preserved upon transformation into melanoma. Through its control of the NER/TFIIH complex MITF might coordinately regulate repair and transcription processes, thereby optimizing the rapid resumption of transcriptional activity after completion of strand repair, which is vitally important for cellular survival. The very same mechanism may drive the genesis of melanoma and its progression in the context of aberrant transcriptional activity of MITF.