FBH1

Domain

The PIP-box mediates the interaction with PCNA.

Function

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).

Involvement in disease

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.

Pathway

Protein modification; protein ubiquitination.

Post-translational modifications

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).

Sequence Similarities

Belongs to the helicase family. UvrD subfamily.

Cellular localization

• 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).

Alternative names

FBX18, FBXO18, FBH1, F-box DNA helicase 1, hFBH1, DNA 3'-5' helicase 1, F-box only protein 18

Database links

swissprot:Q8NFZ0 entrezGene:84893 omim:607222 genbank:BC113377