BRCA1-mediated ubiquitination inhibits topoisomerase II alpha activity in response to oxidative stress.
Topoisomerase IIalpha is known to be critically involved in both cell proliferation and cell death. The mechanisms responsible for stress-dependent topoisomerase IIalpha alterations, however, remain unclear. This study focused on the behavior of topoisomerase IIalpha in response to oxidative stress induced by hydrogen peroxide (H(2)O(2)). The catalytic activity of topoisomerase IIalpha in MOLT-4 cells treated with H(2)O(2) decreased in parallel with the alteration of topoisomerase IIalpha expression. The ubiquitination of topoisomerase IIalpha was dependent on oxidative stress. BRCA1, a tumor-suppressor gene, appeared to be involved in these alterations in topoisomerase IIalpha. Furthermore, the retinoblastoma protein (pRb) was required for the ubiquitination of topoisomerase IIalpha by BRCA1. We conclude that the functions of topoisomerase IIalpha are regulated by ubiquitination on exposure to oxidative stress.
Shinagawa
Hirokuni
H
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Miki
Yoshio
Y
Yoshida
Kiyotsugu
K
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D019313:BRCA1 Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D059005:Topoisomerase II Inhibitors; D054875:Ubiquitination
D000951:Antigens, Neoplasm; D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D016877:Oxidants; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D059005:Topoisomerase II Inhibitors; D006861:Hydrogen Peroxide; D004250:DNA Topoisomerases, Type II