- Topoisomerases play a vital role in transcription by regulating DNA supercoiling and ensuring smooth progression of RNA polymerase along the DNA template. As RNA polymerase moves along the DNA during transcription, it unwinds the double helix, generating positive supercoiling ahead of the enzyme and negative supercoiling behind it. This torsional stress can hinder the elongation process, stall RNA polymerase, and affect gene expression if not properly managed.
- To relieve this topological stress, cells employ topoisomerase I (TOP1) and topoisomerase II (TOP2). TOP1 makes transient single-strand breaks in the DNA, allowing it to swivel and release the accumulated supercoils. This activity is particularly important in highly transcribed genes where the demand for torsional relaxation is high. By relieving supercoiling, TOP1 facilitates the smooth passage of RNA polymerase and supports efficient transcription elongation.
- TOP2, particularly the TOP2B isoform, also contributes to transcription regulation. Unlike TOP1, TOP2 introduces transient double-strand breaks in the DNA to resolve complex topological problems such as DNA knots and tangles that can arise during transcription of long or repetitive genes. TOP2B has been implicated in transcriptional activation of certain genes, especially those that respond to hormone or stress signals. It can create controlled double-strand breaks at promoter regions to facilitate chromatin remodeling and transcription factor access.
- Beyond resolving supercoils, topoisomerases also influence chromatin structure and transcriptional regulation. For example, by modulating DNA topology, they indirectly affect nucleosome positioning and histone modifications, which are key components of epigenetic regulation. Misregulation of topoisomerase activity can therefore disrupt gene expression patterns and contribute to pathological conditions, including cancer and neurological disorders.
