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Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity

Anbarasi Kothandapani1, Kathirvel Gopalakrishnan, Bhaskar Kahali

  • 1Department of Biochemistry and Cancer Biology, University of Toledo-Health Science Campus, Toledo, OH 43614, USA.

Experimental Cell Research
|June 23, 2012
PubMed

Insights

The SWI/SNF chromatin remodeling complex, involving Brg1 and Brm, enhances cancer cell sensitivity to cisplatin by aiding DNA repair. Its depletion impairs the repair of cisplatin DNA adducts and double-strand breaks.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Chromatin Dynamics

Background:

  • The SWI/SNF chromatin remodeling complex is crucial for various cellular processes, including DNA repair.
  • Cisplatin is a widely used chemotherapy agent that induces DNA damage.

Purpose of the Study:

  • To investigate the role of SWI/SNF subunits Brg1 and Brm in the cellular response to cisplatin in lung and head/neck cancer cells.
  • To elucidate the mechanism by which SWI/SNF influences cisplatin-induced DNA damage repair.

Main Methods:

  • Stable knockdown of Brg1 and Brm in cancer cell lines.
  • Assessment of cellular sensitivity to cisplatin.
  • Analysis of DNA adduct repair kinetics and DNA double-strand break repair.
  • Evaluation of chromatin relaxation, checkpoint activation, and apoptosis.
  • Investigation of DNA damage recognition factor recruitment (XPC and ERCC1).

Main Results:

  • Knockdown of Brg1 and Brm increased cisplatin sensitivity.
  • Downregulation of Brg1 and Brm impaired the repair of cisplatin DNA adducts (intrastrand and interstrand crosslinks) and ICL-induced double-strand breaks.
  • Brg1 and Brm deficiency led to altered checkpoint activation, enhanced apoptosis, and impaired chromatin relaxation.
  • While XPC recruitment was unaffected, ERCC1 recruitment was impaired in Brg1 and Brm depleted cells.

Conclusions:

  • The SWI/SNF chromatin remodeling complex, through Brg1 and Brm, plays a significant role in modulating cisplatin cytotoxicity.
  • SWI/SNF facilitates efficient repair of cisplatin-induced DNA lesions, impacting therapeutic outcomes.
  • Targeting SWI/SNF may represent a strategy to enhance the efficacy of cisplatin chemotherapy.

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