Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity.
Chromatin remodeling complex SWI/SNF plays important roles in many cellular processes including transcription, proliferation, differentiation and DNA repair. In this report, we investigated the role of SWI/SNF catalytic subunits Brg1 and Brm in the cellular response to cisplatin in lung cancer and head/neck cancer cells. Stable knockdown of Brg1 and Brm enhanced cellular sensitivity to cisplatin. Repair kinetics of cisplatin DNA adducts revealed that downregulation of Brg1 and Brm impeded the repair of both intrastrand adducts and interstrand crosslinks (ICLs). Cisplatin ICL-induced DNA double strand break repair was also decreased in Brg1 and Brm depleted cells. Altered checkpoint activation with enhanced apoptosis as well as impaired chromatin relaxation was observed in Brg1 and Brm deficient cells. Downregulation of Brg1 and Brm did not affect the recruitment of DNA damage recognition factor XPC to cisplatin DNA lesions, but affected ERCC1 recruitment, which is involved in the later stages of DNA repair. Based on these results, we propose that SWI/SNF chromatin remodeling complex modulates cisplatin cytotoxicity by facilitating efficient repair of the cisplatin DNA lesions.
Department of Biochemistry and Cancer Biology, University of Toledo-Health Science Campus, Toledo, OH 43614, USA.
Anbarasi
A
Kothandapani
Kathirvel
K
Gopalakrishnan
Bhaskar
B
Kahali
David
D
Reisman
Steve M
SM
Patrick
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D018736:DNA Adducts / Q000235:genetics; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D021122:Protein Subunits; D034741:RNA, Small Interfering; C084011:SMARCA2 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; C057270:cisplatin-DNA adduct; C086984:XPC protein, human; C071447:ERCC1 protein, human; D004720:Endonucleases; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D002945:Cisplatin