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

Cristina Ribeiro-Silva1, Özge Z Aydin1,2, Raquel Mesquita-Ribeiro3

  • 1Department of Molecular Genetics, Oncode Institute, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.

Nature Communications
|October 6, 2018
PubMed

Insights

SWI/SNF gene mutations are common in cancer. This study reveals GTF2H1 as a potential marker for predicting platinum drug sensitivity in SWI/SNF-deficient cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Mutations in SWI/SNF genes are prevalent in human cancers, yet targeted therapies remain limited.
  • SWI/SNF ATPases, BRM/SMARCA2 and BRG1/SMARCA4, are crucial for cellular processes.
  • Understanding SWI/SNF mutation-associated vulnerabilities is critical for developing new cancer treatments.

Purpose of the Study:

  • To investigate the role of SWI/SNF ATPases in regulating GTF2H1 expression.
  • To determine the impact of SWI/SNF inactivation on TFIIH complex stability and function.
  • To identify potential therapeutic targets and predictive markers in SWI/SNF-mutated cancers.

Main Methods:

  • Gene expression analysis to assess GTF2H1 levels following SWI/SNF ATPase inactivation.
  • Assessment of TFIIH complex stability and its roles in transcription and nucleotide excision repair (NER).
  • Evaluation of cellular sensitivity to DNA-damaging agents (UV irradiation, cisplatin) in SWI/SNF-deficient cells with varying GTF2H1 levels.

Main Results:

  • SWI/SNF ATPases BRM/SMARCA2 and BRG1/SMARCA4 positively regulate p62/GTF2H1 expression.
  • Inactivation of BRM or BRG1 leads to decreased GTF2H1 levels, compromising TFIIH function in transcription and NER.
  • Cancer cells with SWI/SNF deficiencies can restore GTF2H1 expression, influencing their DNA damage sensitivity.

Conclusions:

  • GTF2H1 is a key downstream target regulated by SWI/SNF ATPases.
  • GTF2H1 levels are critical for the DNA repair capacity and drug sensitivity of SWI/SNF-mutated cancer cells.
  • GTF2H1 emerges as a promising predictive biomarker for platinum-based chemotherapy response in SWI/SNF-deficient cancers.

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