FAM111A is a single-stranded DNA-binding serine protease that mediates proteolytic cleavage of DNA-protein cross-links (DPCs) during DNA synthesis, thereby maintaining genomic integrity 1. The protein protects replication forks from stalling by removing covalently trapped topoisomerase 1 and PARP1-DNA complexes 1, and is required for PCNA loading on replication sites and S-phase entry 2. FAM111A facilitates efficient activation of DNA replication origins 3. Beyond DNA repair, FAM111A functions as a restriction factor against poxviruses including vaccinia virus and mpox virus 4. Upon viral infection, FAM111A translocates to the cytoplasm and disrupts the nuclear pore complex via its protease activity, interacts with viral DNA-binding proteins, and promotes their degradation through autophagy 4. Poxviruses antagonize FAM111A through their serpin SPI-1, which directly inhibits FAM111A's protease activity via covalent complex formation 5. Disease-relevant mutations in FAM111A cause Kenny-Caffey syndrome type 2 and osteocraniostenosis, rare genetic disorders characterized by extreme short stature, bone abnormalities, hypoparathyroidism, and electrolyte disturbances 67. Both gain-of-function and loss-of-function FAM111A variants contribute to disease pathogenesis 7.