DNA damage impedes replication fork progression and threatens genome stability. Upon encounter with most DNA adducts, the replicative CMG helicase (CDC45-MCM2-7-GINS) stalls or uncouples from the point of synthesis, yet eventually resumes replication. However, little is known about the effect on replication of single-strand breaks or “nicks,” which are abundant in mammalian cells. Using Xenopus egg extracts, we reveal that CMG collision with a nick in the leading strand template generates a blunt-ended double-strand break (DSB). Moreover, CMG, which encircles the leading strand template, “runs off” the end of the DSB. In contrast, CMG collision with a lagging strand nick generates a broken end with a single-stranded overhang. In this setting, CMG translocates along double-stranded DNA beyond the break and is then ubiquitylated and removed from chromatin by the same pathway used during replication termination. Our results show that nicks are uniquely dangerous DNA lesions that invariably cause replisome disassembly, and they suggest that CMG cannot be stored on dsDNA while cells resolve replication stress. Display omitted •The structures of leading and lagging strand collapsed forks are different•CMG passively “runs off” the broken DNA end during leading strand fork collapse•CMG removal from duplex DNA after lag collapse depends on CRL2Lrr1 and p97•Nicks are uniquely toxic lesions that cause fork collapse and replisome disassembly Vrtis et al. show that when a replisome encounters a single-strand DNA break in the leading or lagging strand template, the replication fork collapses, generating a double-strand break. Collapse is accompanied by loss of the replicative helicase from DNA, implying that fork restart would require recruitment of a new helicase.