DNA topoisomerase IIα(170 kDa,TOP2α/170)induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation,replication,and segregation.Therefore...DNA topoisomerase IIα(170 kDa,TOP2α/170)induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation,replication,and segregation.Therefore,TOP2α/170 is a prominent target for anticancer drugs whose clinical efficacy is often compromised due to chemoresistance.Although many resistance mechanisms have been defined,acquired resistance of human cancer cell lines to TOP2αinterfacial inhibitors/poisons is frequently associated with a reduction of Top2α/170 expression levels.Recent studies by our laboratory,in conjunction with earlier findings by other investigators,support the hypothesis that a major mechanism of acquired resistance to TOP2α-targeted drugs is due to alternative RNA processing/splicing.Specifically,several TOP2αmRNA splice variants have been reported which retain introns and are translated into truncated TOP2αisoforms lacking nuclear localization sequences and subsequent dysregulated nuclear-cytoplasmic disposition.In addition,intron retention can lead to truncated isoforms that lack both nuclear localization sequences and the active site tyrosine(Tyr805)necessary for forming enzyme-DNA covalent complexes and inducing DNA damage in the presence of TOP2α-targeted drugs.Ultimately,these truncated TOP2αisoforms result in decreased drug activity against TOP2αin the nucleus and manifest drug resistance.Therefore,the complete characterization of the mechanism(s)regulating the alternative RNA processing of TOP2αpre-mRNA may result in new strategies to circumvent acquired drug resistance.Additionally,novel TOP2αsplice variants and truncated TOP2αisoforms may be useful as biomarkers for drug resistance,prognosis,and/or direct future TOP2α-targeted therapies.展开更多
基金This work was supported by the National Institutes of Health National Cancer Institute(Grant R01 CA226906-01A1).
文摘DNA topoisomerase IIα(170 kDa,TOP2α/170)induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation,replication,and segregation.Therefore,TOP2α/170 is a prominent target for anticancer drugs whose clinical efficacy is often compromised due to chemoresistance.Although many resistance mechanisms have been defined,acquired resistance of human cancer cell lines to TOP2αinterfacial inhibitors/poisons is frequently associated with a reduction of Top2α/170 expression levels.Recent studies by our laboratory,in conjunction with earlier findings by other investigators,support the hypothesis that a major mechanism of acquired resistance to TOP2α-targeted drugs is due to alternative RNA processing/splicing.Specifically,several TOP2αmRNA splice variants have been reported which retain introns and are translated into truncated TOP2αisoforms lacking nuclear localization sequences and subsequent dysregulated nuclear-cytoplasmic disposition.In addition,intron retention can lead to truncated isoforms that lack both nuclear localization sequences and the active site tyrosine(Tyr805)necessary for forming enzyme-DNA covalent complexes and inducing DNA damage in the presence of TOP2α-targeted drugs.Ultimately,these truncated TOP2αisoforms result in decreased drug activity against TOP2αin the nucleus and manifest drug resistance.Therefore,the complete characterization of the mechanism(s)regulating the alternative RNA processing of TOP2αpre-mRNA may result in new strategies to circumvent acquired drug resistance.Additionally,novel TOP2αsplice variants and truncated TOP2αisoforms may be useful as biomarkers for drug resistance,prognosis,and/or direct future TOP2α-targeted therapies.
