FAM111A
Description
The FAM111A (FAM111 trypsin like peptidase A) is a protein-coding gene located on chromosome 11.
FAM111A is a protein encoded by the FAM111A gene in humans. It is cell-cycle regulated and localizes to the nucleus. The C-terminal half of the protein shares homology with trypsin-like peptidases and contains a PCNA-interacting peptide (PIP) box, essential for co-localization with proliferating cell nuclear antigen (PCNA). Reduced FAM111A expression leads to DNA replication defects, highlighting its role in Simian Virus 40 (SV40) viral replication. Monoallelic variants in FAM111A are linked to dominantly inherited Kenny-Caffey syndrome (KCS) and the more severe osteocraniostenosis (OCS), both characterized by short stature, hypoparathyroidism, bone development abnormalities, and hypocalcemia. Multiple transcript variants arise from alternative splicing of the FAM111A transcript.
FAM111A is a single-stranded DNA-binding serine protease that plays a critical role in maintaining genomic integrity by cleaving covalent DNA-protein cross-links (DPCs) during DNA synthesis. DPCs are highly toxic DNA lesions that disrupt essential chromatin processes like replication and transcription, often induced by reactive agents such as UV light or formaldehyde. FAM111A protects the replication fork from stalling by removing DPCs, including covalently trapped topoisomerase 1 (TOP1) adducts on DNA lesions and poly(ADP-ribose) polymerase 1 (PARP1)-DNA complexes trapped by PARP inhibitors. It is essential for PCNA loading onto replication sites and promotes S-phase entry and DNA synthesis. Furthermore, FAM111A acts as a restriction factor against viruses such as SV40 polyomavirus and vaccinia virus. It disrupts the nuclear pore complex (NPC) via its protease activity, affecting the nuclear barrier function during viral replication. Notably, FAM111A interacts with vaccinia virus DNA-binding protein OPG079 in the cytoplasm, promoting its degradation through autophagy, independent of its protease activity.
FAM111A is also known as GCLEB, KCS2.
