FBXO18

This gene encodes a member of the F-box protein family, members of which are characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into three classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbx class. It contains an F-box motif and seven conserved helicase motifs, and has both DNA-dependent ATPase and DNA unwinding activities. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene.

F-box protein 18

3'-5' DNA helicase and substrate-recognition component of the SCF(FBH1) E3 ubiquitin ligase complex that plays a key role in response to stalled/damaged replication forks (PubMed:11956208, PubMed:23393192).

Involved in genome maintenance by acting as an anti-recombinogenic helicase and preventing extensive strand exchange during homologous recombination: promotes RAD51 filament dissolution from stalled forks, thereby inhibiting homologous recombination and preventing excessive recombination (PubMed:17724085, PubMed:19736316).

Also promotes cell death and DNA double-strand breakage in response to replication stress: together with MUS81, promotes the endonucleolytic DNA cleavage following prolonged replication stress via its helicase activity, possibly to eliminate cells with excessive replication stress (PubMed:23319600, PubMed:23361013).

Plays a major role in remodeling of stalled DNA forks by catalyzing fork regression, in which the fork reverses and the two nascent DNA strands anneal (PubMed:25772361).

In addition to the helicase activity, also acts as the substrate-recognition component of the SCF(FBH1) E3 ubiquitin ligase complex, a complex that mediates ubiquitination of RAD51, leading to regulate RAD51 subcellular location (PubMed:25585578).

Cell death Source: UniProtKB
Cellular response to DNA damage stimulus Source: UniProtKB
DNA catabolic process, endonucleolytic Source: MGI
Double-strand break repair via homologous recombination Source: UniProtKB
Negative regulation of chromatin binding Source: Ensembl
Negative regulation of double-strand break repair via homologous recombination Source: UniProtKB
Positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage Source: MGI
Positive regulation of protein phosphorylation Source: MGI
Protein ubiquitination Source: UniProtKB
Recombinational repair Source: GO_Central
Replication fork processing Source: UniProtKB
Replication fork protection Source: UniProtKB
Response to intra-S DNA damage checkpoint signaling Source: MGI

Nucleus; Chromosome. Accumulates at sites of DNA damage or replication stress (PubMed:19736316, PubMed:23677613). PCNA is required for localization to DNA damage sites (PubMed:23677613). Localizes to the nucleoplasm in absence of DNA damage (PubMed:23677613).

Defects in FBH1 are frequently observed in melanomas, resulting in increased survival in response to replicative stress. Its inactivation may play a role in oncogenic transformation.

Ubiquitinated (PubMed:23393192, PubMed:23677613). Ubiquitination by the DCX(DTL) complex, also named CRL4(CDT2), leading to its degradation: ubiquitination takes place after its localization to DNA damage sites, possibly to facilitate the translesion synthesis (TLS) pathway (PubMed:23677613).