Updated project metadata. FAM111A is a replisome associated protein and dominant mutations within its trypsin-like peptidase domain are linked to severe human developmental syndrome, the Kenny-Caffey syndrome. However, FAM111A functions remain unclear. Here, we show that FAM111A facilitates efficient activation of DNA replication origins. Upon replication fork stalling, FAM111A promotes dormant origin activation and ssDNA exposure. Furthermore, unrestrained expression of FAM111A wild-type as well as patient mutants causes accumulation of DNA damage and cell death, only when the peptidase domain remains intact. The peptidase domain is responsible for ssDNA exposure during S phase, which is not caused by caspase dependent apoptosis. Altogether, these data unveil how FAM111A promotes DNA replication in normal conditions and becomes harmful in a disease context.