The structure of the nucleus in normal and neoplastic prostate cells: untangling the role of type 2 DNA topoisomerases.

Donald S. Coffey, a pioneer in the study of the structural basis of mammalian genome organization, was fascinated by DNA topoisomerases, chemo-mechanical enzymes that could catalyze changes in DNA structure. Work initiated in his laboratory and carried on with his influence and inspiration has led to the elucidation of specific roles for each of the two type 2 topoisomerases in DNA replication, RNA transcription, and androgen action in prostate cells. TOP2A principally acts in DNA synthesis elongation to prevent tangling of daughter DNA molecules during genome replication and mitotic segregation; TOP2B is required for androgen-stimulation of target gene transcription. DNA double-strand breaks inflicted by TOP2B upon androgen exposure appear responsible for the generation of TMPRSS2-ERG and other gene fusions, often found in complex chained rearrangements termed chromoplexy, in prostate cancer cells. TOP2B-mediated genome damage may also provide an avenue for improving prostate cancer treatment via timed androgen administration in conjunction with ionizing radiation, with TOP2-targeted drugs, or with DNA repair inhibitors.