Highlights • TOP2A accumulates at stalled replication forks and promotes fork reversal • TOP2A is SUMOylated by ZATT on chromatin in response to replication stress • SUMOylated TOP2A recruits the DNA translocase PICH to stalled replication forks • The ZATT-TOP2A-PICH axis drives extensive replication fork reversal Summary Replication fork reversal is a global response to replication stress in mammalian cells, but precisely how it occurs remains poorly understood.