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

TY - JOUR

T1 - Lineage-specific control of TFIIH by MITF determines transcriptional homeostasis and DNA repair

AU - Seoane, Marcos

AU - Buhs, Sophia

AU - Iglesias, Pablo

AU - Strauss, Julia

AU - Puller, Ann-Christin

AU - Müller, Jürgen

AU - Gerull, Helwe

AU - Feldhaus, Susanne

AU - Alawi, Malik

AU - Brandner, Johanna M

AU - Eggert, Dennis

AU - Du, Jinyan

AU - Thomale, Jürgen

AU - Wild, Peter J

AU - Zimmermann, Martin

AU - Sternsdorf, Thomas

AU - Schumacher, Udo

AU - Nollau, Peter

AU - Fisher, David E

AU - Horstmann, Martin A

PY - 2019/5

Y1 - 2019/5

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1038/s41388-018-0661-x

DO - 10.1038/s41388-018-0661-x

M3 - SCORING: Journal article

C2 - 30651597

VL - 38

SP - 3616

EP - 3635

JO - ONCOGENE

JF - ONCOGENE

SN - 0950-9232

IS - 19

ER -