Effects of DNA topoisomerase II? splice variants on acquired drug resistance.

ABSTRACT: DNA topoisomerase II? (170 kDa, TOP2?/170) induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation, replication, and segregation. Therefore, TOP2?/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 TOP2? interfacial inhibitors/poisons is frequently associated with a reduction of Top2?/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 TOP2?-targeted drugs is due to alternative RNA processing/splicing. Specifically, several TOP2? mRNA splice variants have been reported which retain introns and are translated into truncated TOP2? isoforms 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 TOP2?-targeted drugs. Ultimately, these truncated TOP2? isoforms result in decreased drug activity against TOP2? in the nucleus and manifest drug resistance. Therefore, the complete characterization of the mechanism(s) regulating the alternative RNA processing of TOP2? pre-mRNA may result in new strategies to circumvent acquired drug resistance. Additionally, novel TOP2? splice variants and truncated TOP2? isoforms may be useful as biomarkers for drug resistance, prognosis, and/or direct future TOP2?-targeted therapies.

SUBMITTER: Elton TS 

PROVIDER: S-EPMC7304410 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature