Lineage-specific control of TFIIH by MITF determines transcriptional homeostasis and DNA repair.
Animals
Cells, Cultured
DNA Repair
/ physiology
Discoidin Domain Receptor 1
/ genetics
Female
Genes, myc
Humans
Melanocytes
/ physiology
Melanoma
/ metabolism
Mice, SCID
Microphthalmia-Associated Transcription Factor
/ genetics
Phosphoproteins
/ genetics
Skin Neoplasms
/ metabolism
Transcription Factor TFIIH
/ genetics
Transcription Factors
/ genetics
Transcription Factors, TFII
/ genetics
Transcription, Genetic
Ultraviolet Rays
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
25
09
2018
accepted:
05
12
2018
pubmed:
18
1
2019
medline:
24
10
2019
entrez:
18
1
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30651597
doi: 10.1038/s41388-018-0661-x
pii: 10.1038/s41388-018-0661-x
pmc: PMC6756118
doi:
Substances chimiques
GTF2H1 protein, human
0
Gtf2h1 protein, mouse
0
MITF protein, human
0
Microphthalmia-Associated Transcription Factor
0
Phosphoproteins
0
Transcription Factors
0
Transcription Factors, TFII
0
Transcription Factor TFIIH
148710-81-0
DDR1 protein, human
EC 2.7.10.1
Discoidin Domain Receptor 1
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3616-3635Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR043369
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222871
Pays : United States
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