Topoisomerase I and Genome Stability: The Good and the Bad

Topoisomerase I (Top1) resolves torsional stress that accumulates during transcription, replication and chromatin remodeling by introducing a transient single-strand break in DNA. The cleavage activity of Top1 has opposing roles, either promoting or destabilizing genome integrity depending on the context. Resolution of transcription-associated negative supercoils, for example, prevents pairing of the nascent RNA with the DNA template (R-loops) as well as DNA secondary structure formation. Reduced Top1 levels thus enhance CAG repeat contraction, somatic hypermutation, and class switch recombination. Actively transcribed ribosomal DNA is also destabilized in the absence of Top1, reflecting the importance of Top1 in ensuring efficient transcription. In terms of promoting genome instability, an aborted Top1 catalytic cycle stimulates deletions at short tandem repeats and the enzyme's transesterification activity supports illegitimate recombination. Finally, Top1 incision at ribonucleotides embedded in DNA generates deletions in tandem repeats, and induces gross chromosomal rearrangements and mitotic recombination.