Distinct roles of Topoisomerase II isoforms: DNA damage accelerating α, double strand break repair promoting β

Abstract

Topoisomerase II α (TopoIIα) and Topoisomerase II β (TopoIIβ) isoforms are different gene products having conserved catalytic activities. The α isoform is present in proliferating cell, while β isoform is predominantly present in non-proliferating cells namely neurons suggesting its role in non-replicating functions of DNA. The functions of TopoIIα and TopoIIβ isoforms are analyzed in peroxide-mediated DNA damage and double strand breaks (DSBs) repair in neuroblastoma and astrocytoma cells. The results show a strong correlation of TopoIIα level with the progression of DNA damage, while the TopoIIβ expression is correlated with the DNA DSBs repair activity of cells in Ku70, Werner's helicase and pol-β dependent pathways. The functional roles of TopoIIα and TopoIIβ are assessed using siRNA mediated TopoIIα and TopoIIβ knockdown in cells. The results show that TopoIIα-TopoIIβ+ cells are resistant to peroxide-mediated DNA damage, while TopoIIα+TopoIIβ- cells are 2-fold more sensitive to peroxide and TopoIIβ deficiency lead to cellular apoptosis. These results are correlated with cell survival from peroxide-mediated insult. The result of this study that TopoIIα accelerates peroxide-mediated DNA damage, while TopoIIβ promotes DNA DSBs repair activity should provide new directions toward understanding of normalytic ageing processes in human brain. © 2007 Elsevier Inc. All rights reserved.