Abstract

The unscheduled arrest of DNA replication forks is a frequent and mutagenic phenomenonaffecting all growing cells. DNA-bound proteins and elongating transcription complexes are thetwo major triggers of unscheduled fork arrest, and it is generally thought that these effectsoperate by physical occlusion. We show here that, instead, replication fork arrest results from theaccumulation of superhelical stress between the fork and barrier, thousands of base pairs away.Reducing positive supercoiling prevented fork arrest, allowing fork progression through both astable protein complex and a highly transcribed site oriented toward oncoming replication forks.Reducing positive supercoiling improved fork progression globally and decreased the occurrenceof spontaneous fork stalling, indicating that spontaneous fork blockages are frequent and alsosupercoiling-mediated. These results transform our understanding of how DNA-bound obstaclesimpede replication forks — by restricting the passage of inhibitory supercoiling instead of bydirect collision.

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