FANCL is the catalytic E3 ubiquitin ligase subunit of the Fanconi anemia (FA) core complex. It catalyzes the monoubiquitination of [FANCD2](/genes/fancd2) and [FANCI](/genes/fanci), the essential activation step in the FA DNA damage response pathway. FANCL contains a RING finger domain that confers E3 ubiquitin ligase activity and works with the E2 conjugating enzyme UBE2T to transfer ubiquitin to FANCD2. Dysregulation of FANCL and the FA pathway has implications for neurodegeneration, cancer predisposition, and therapeutic targeting.
Molecular Structure
FANCL is a 380-amino acid protein with a molecular weight of approximately 43 kDa. The protein contains several functional domains:
N-terminal L(1) domain: Mediates protein-protein interactions within the FA core complex
RING finger domain: Contains the catalytic E3 ubiquitin ligase activity (Cys3-His-Cys4 motif)
UEV domain: Ubiquitin-conjugating enzyme variant that binds UBE2T
PHD finger: Histone binding and chromatin recognition
The RING finger domain coordinates two Zn²⁺ ions and catalyzes ubiquitin transfer from the E2 enzyme to the substrate. The UEV domain specifically recognizes UBE2T (E2 conjugating enzyme) and positions it for ubiquitin transfer.
Catalytic Mechanism
FANCL catalyzes monoubiquitination through:
E2 enzyme binding: UBE2T∼Ub (thioester-linked ubiquitin) binds to FANCL
Substrate recognition: FANCD2-I complex is recruited
Ubiquitin transfer: RING domain catalyzes isopeptide bond formation
Product release: FANCD2-Ub and FANCI-Ub are released
UBE2T∼Ub + FANCD2 → FANCD2-Ub + UBE2T
FANCL-mediated ubiquitination targets:
FANCD2 (K561)
FANCI (K688)
Physiological Function
DNA Interstrand Crosslink Repair
FANCL is essential for the FA DNA damage response:
ICL repair: Central to DNA interstrand crosslink (ICL) repair
[Mitophagy](/mechanisms/mitophagy-pathway) - Mitochondrial quality control
References
[França et al., Genetics of ovarian insufficiency and defects of folliculogenesis (2022)](https://pubmed.ncbi.nlm.nih.gov/34794894/)
[Zhang et al., Fanconi anemia and ubiquitination (2007)](https://pubmed.ncbi.nlm.nih.gov/17643942/)
[van de Kooij et al., The Fanconi anemia core complex promotes CtIP-dependent end resection (2024)](https://pubmed.ncbi.nlm.nih.gov/39152113/)
[Miles et al., The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin (2015)](https://pubmed.ncbi.nlm.nih.gov/26149689/)
[Zhao et al., Functions of FANCL in primordial germ cell formation and Fanconi anemia (2005)](https://pubmed.ncbi.nlm.nih.gov/16201245/)
[Beesetti et al., FANCL supports Parkin-mediated mitophagy (2022)](https://pubmed.ncbi.nlm.nih.gov/35644338/)
[Chauhan et al., E3 ligases: a ubiquitous link between DNA repair, DNA replication and human disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38985307/)
[Graham et al., DNA-Damaging Therapies in Patients With Prostate Cancer (2024)](https://pubmed.ncbi.nlm.nih.gov/39178368/)
[Marek et al., Drosophila homologs of FANCD2 and FANCL function in DNA repair (2006)](https://pubmed.ncbi.nlm.nih.gov/16860002/)
[Garner et al., Ubiquitylation and the Fanconi anemia pathway (2011)](https://pubmed.ncbi.nlm.nih.gov/21605559/)
[Silva et al., Germline Variants in DNA Interstrand-Cross Link Repair Genes (2024)](https://pubmed.ncbi.nlm.nih.gov/39519399/)
[Liu et al., Deficient FANCL Predisposes to Endothelial Damage (2025)](https://pubmed.ncbi.nlm.nih.gov/40479584/)
[Del Valle et al., Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients (2020)](https://pubmed.ncbi.nlm.nih.gov/32235514/)
[Chen et al., Comparison of BRCA versus non-BRCA germline mutations (2020)](https://pubmed.ncbi.nlm.nih.gov/32091409/)
[Wang et al., Structure of the FANCL ubiquitin ligase (2008)](https://pubmed.ncbi.nlm.nih.gov/18648669/)
[Alpi et al., Mechanistic insight into FANCL-dependent activation of FANCD2 (2008)](https://pubmed.ncbi.nlm.nih.gov/18596687/)
[Medhurst et al., The Fanconi anemia pathway requires FANCL (2008)](https://pubmed.ncbi.nlm.nih.gov/18480479/)
[Hiramoto et al., Nuclease-susceptible FANCD2-ubiquitin (2017)](https://pubmed.ncbi.nlm.nih.gov/28193876/)
[Taniguchi et al., Silencing FANCL for cancer therapy (2017)](https://pubmed.ncbi.nlm.nih.gov/28242760/)
[Ceccaldi et al., The Fanconi anemia pathway and cancer (2016)](https://pubmed.ncbi.nlm.nih.gov/27161184/)