STRUCTURAL ORGANIZATION OF THE HUMAN TOP2A AND TOP2B GENES

Eucaryotic topoisomerase II is an essential nuclear enzyme involved in processes such as chromosome condensation, chromatid separation, and in the relief of torsional stress that occurs during DNA transcription and replication. In cells from vertebrate species, there are two form s of the enzyme, designated alpha and beta. Human topoisomerase II alp ha (TOP2A) is encoded by the TOP2A gene on chromosome 17q21-22, and hu man topoisomerase II beta (TOP2B) is encoded by the TOP2B gene on chro mosome 3p24. The protein products of these two genes are important cel lular targets of several drugs widely used in the treatment of many hu man cancers, and a variety of mutations in TOP2A have been associated with the development of drug resistance. In the present study, we have defined the intron-exon structures of TOP2A and TOP2B. TOP2A is appro x. 30 kb whereas TOP2B is at least 49 kb. TOP2A and TOP2B contain 35 a nd 36 exons, respectively, and both genes contain a high proportion of class 0 introns. Alignment of the amino-acid sequences of the two pro teins indicates that the intron-exon organization of the two genes is highly conserved, except for the regions encoding the extreme NH, and COOH termini of the proteins. These findings suggest strongly that the vertebrate isoforms evolved by duplication of an ancestral gene. Muta tions in TOP2A associated with drug resistance show clustering in exon s 12, 13, 19-21 and 34-35. Knowledge of the genomic organization of TO P2A and TOP2B will be useful for detection of mutations in clinical sa mples from patients with drug-resistant malignant disease. (C) 1998 El sevier Science B.V. All rights reserved.