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Oncogene. 2019 May;38(19):3616-3635. doi: 10.1038/s41388-018-0661-x. Epub 2019 Jan 16.

Lineage-specific control of TFIIH by MITF determines transcriptional homeostasis and DNA repair.

Author information

1
Research Institute Children's Cancer Center Hamburg, Hamburg, 20246, Germany.
2
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, 20246, Germany.
3
Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg, Hamburg, 20246, Germany.
4
Bioinformatics Service Facility, University Medical Center Hamburg, Hamburg, 20246, Germany.
5
Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, 20251, Germany.
6
Department of Dermatology, University Medical Center Hamburg, Hamburg, 20246, Germany.
7
Max-Planck-Institute for the Structure and Dynamics of Matter, Hamburg, 22761, Germany.
8
Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
9
Merrimack Pharmaceuticals, Cambridge, MA, 02139, USA.
10
Institute of Cell Biology, University Duisburg-Essen, Essen, 45122, Germany.
11
Institute of Surgical Pathology, University Hospital Zürich, Zürich, 8091, Switzerland.
12
Department of Pediatric Hematology and Oncology, Medical School Hannover, Hannover, 30625, Germany.
13
Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02115, USA.
14
Research Institute Children's Cancer Center Hamburg, Hamburg, 20246, Germany. horstman@uke.de.
15
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, 20246, Germany. horstman@uke.de.

Abstract

The melanocytic lineage, which is prominently exposed to ultraviolet radiation (UVR) and radiation-independent oxidative damage, requires specific DNA-damage response mechanisms to maintain genomic and transcriptional homeostasis. The coordinate lineage-specific regulation of intricately intertwined DNA repair and transcription is incompletely understood. Here we demonstrate that the Microphthalmia-associated transcription factor (MITF) directly controls general transcription and UVR-induced nucleotide excision repair by transactivation of GTF2H1 as a core element of TFIIH. Thus, MITF ensures the rapid resumption of transcription after completion of strand repair and maintains transcriptional output, which is indispensable for survival of the melanocytic lineage including melanoma in vitro and in vivo. Moreover, MITF controls c-MYC implicated in general transcription by transactivation of far upstream binding protein 2 (FUBP2/KSHRP), which induces c-MYC pulse regulation through TFIIH, and experimental depletion of MITF results in consecutive loss of CDK7 in the TFIIH-CAK subcomplex. Targeted for proteasomal degradation, CDK7 is dependent on transactivation by MITF or c-MYC to maintain a steady state. The dependence of TFIIH-CAK on sequence-specific MITF and c-MYC constitutes a previously unrecognized mechanism feeding into super-enhancer-driven or other oncogenic transcriptional circuitries, which supports the concept of a transcription-directed therapeutic intervention in melanoma.

PMID:
30651597
DOI:
10.1038/s41388-018-0661-x

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