THE ROLE OF TOPOISOMERASE II BETA IN FACILITATING THE ANDROGEN-INDUCED TRANSCRIPTIONAL PROGRAM
Embargo until
2025-05-01
Date
2021-03-24
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Johns Hopkins University
Abstract
Androgens, such as testosterone and its cellular metabolite dihydrotestosterone (DHT), are cellular signals that can trigger a transcriptional program in androgen-sensitive cells, inducing expression changes in up to hundreds of genes. The coordination of transcription of many genes requires topological changes in the DNA, including unwinding, supercoiling, and chromosomal movement. It is likely that topoisomerases, which create transient single- and double-stranded breaks in DNA, are required for efficient induction of these transcriptional programs by mediating these topological changes and the constraints that arise from them. Topoisomerase ii beta (TOP2B) has previously been shown to be required for efficient activation of androgen-induced genes, and evidence suggests that double stranded breaks (DSBs) mediated by TOP2B, when illegitimately repaired, may lead to chromosomal rearrangements seen in prostate cancer. However, the exact role of TOP2B in androgen-induced transcriptional programs and in the formation of complex chromosomal rearrangement is unknown. Here we study the effect of TOP2B on androgen-induced transcriptional programs and determine whether TOP2B activity is associated with genomic rearrangements seen in cancer by integrating whole genome gene expression, binding, and chromosomal interaction data. The results from this work have the potential to improve our understanding of transcription in the three-dimensional space of the nucleus and the formation of cancer-associated genomic rearrangements.
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Keywords
prostate cancer, transcriptional program, topoisomerase, TOP2B, androgen, DHT, androgen receptor, AR, transcriptional hubs, TADs, topologically associating domains, chromoplexy, complex chromosomal rearrangements, TMPRSS2/ERG