DNA replication of circular genomes generates physically interlinked or catenated sister DNAs. These are resolved through transient DNA fracture by type II topoisomerases to permit chromosome segregation during cell division. Topoisomerase II is similarly required for linear chromosome segregation, suggesting that linear chromosomes also remain intertwined following DNA replication. Indeed, chromosome resolution defects are a frequent cause of chromosome segregation failure and consequent aneuploidies. When and where intertwines arise and persist along linear chromosomes are not known, owing to the difficulty of demonstrating intertwining of linear DNAs. Here, we used excision of chromosomal regions as circular "loop outs" to convert sister chromatid intertwines into catenated circles. This revealed intertwining at replication termination and cohesin-binding sites, where intertwines are thought to arise and persist but not to a greater extent than elsewhere in the genome. Intertwining appears to spread evenly along chromosomes but is excluded from heterochromatin. We found that intertwines arise before replication termination, suggesting that replication forks rotate during replication elongation to dissipate torsion ahead of the forks. Our approach provides previously inaccessible insight into the topology of eukaryotic chromosomes and illuminates a process critical for successful chromosome segregation.[Keywords: DNA topology; chromosome segregation; sister chromatid intertwining; precatenanes; topoisomerase II; S. cerevisiae] Supplemental material is available for this article. Genetic information is encoded in DNA as a one-dimensional sequence of bases. However, it is the three-dimensional configuration of the DNA that directs how the information is accessed. This makes DNA topology a crucial player in genome function. The topological state of cellular DNA is under the control of DNA topoisomerases-enzymes that generate transient DNA breaks, rearrange, and then religate their substrates.
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