DNA damage sensitivity of SWI/SNF-deficient cells depends on TFIIH subunit p62/GTF2H1

Cristina Ribeiro-Silva, Özge Z. Aydin, Raquel Mesquita-Ribeiro, Jana Slyskova, Angela Helfricht, Jurgen A. Marteijn, Jan H. J. Hoeijmakers, Hannes Lans () and Wim Vermeulen ()
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Cristina Ribeiro-Silva: Erasmus MC, University Medical Center Rotterdam
Özge Z. Aydin: Erasmus MC, University Medical Center Rotterdam
Raquel Mesquita-Ribeiro: University of Nottingham
Jana Slyskova: Erasmus MC, University Medical Center Rotterdam
Angela Helfricht: Erasmus MC, University Medical Center Rotterdam
Jurgen A. Marteijn: Erasmus MC, University Medical Center Rotterdam
Jan H. J. Hoeijmakers: Erasmus MC, University Medical Center Rotterdam
Hannes Lans: Erasmus MC, University Medical Center Rotterdam
Wim Vermeulen: Erasmus MC, University Medical Center Rotterdam

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Mutations in SWI/SNF genes are amongst the most common across all human cancers, but efficient therapeutic approaches that exploit vulnerabilities caused by SWI/SNF mutations are currently lacking. Here, we show that the SWI/SNF ATPases BRM/SMARCA2 and BRG1/SMARCA4 promote the expression of p62/GTF2H1, a core subunit of the transcription factor IIH (TFIIH) complex. Inactivation of either ATPase subunit downregulates GTF2H1 and therefore compromises TFIIH stability and function in transcription and nucleotide excision repair (NER). We also demonstrate that cells with permanent BRM or BRG1 depletion have the ability to restore GTF2H1 expression. As a consequence, the sensitivity of SWI/SNF-deficient cells to DNA damage induced by UV irradiation and cisplatin treatment depends on GTF2H1 levels. Together, our results expose GTF2H1 as a potential novel predictive marker of platinum drug sensitivity in SWI/SNF-deficient cancer cells.

Date: 2018
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DOI: 10.1038/s41467-018-06402-y

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