FANCL

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Protein-coding gene in the species Homo sapiens

title: "FANCL" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public description: "Protein-coding gene in the species Homo sapiens" topic_path: "uncategorized" source: "https://en.wikipedia.org/wiki/FANCL" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Protein-coding gene in the species Homo sapiens ::

E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.

Structure

The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises three domains: a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain that interacts with FANCB. The ELF domain of FANCL is also required to mediate a non-covalent interaction between FANCL and ubiquitin. The ELF domain promotes efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of FANCB and ubiquitin binding by FANCL in vivo.

A nuclear complex containing FANCL (as well as FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCM) is essential for the activation of FANCD2 to the mono-ubiquitinated isoform. In normal, non-mutant cells FANCD2 is mono-ubiquitinated in response to DNA damage. Activated FANCD2 protein co-localizes with BRCA1 at ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes.

Function

::figure[src="https://upload.wikimedia.org/wikipedia/commons/d/dc/Homologous_recombinational_repair_of_DNA_double-strand_damage.jpg" caption="'''Recombinational repair of DNA double-strand damage - some key steps.'''"] ::

ATM (ATM) is a protein kinase that is recruited and activated by DNA double-strand breaks. DNA double-strand damages also activate the Fanconi anemia core complex (FANCA/B/C/E/F/G/L/M). The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI. ATM activates (phosphorylates) CHEK2 and FANCD2. CHEK2 phosphorylates BRCA1. Ubiquitinated FANCD2 complexes with BRCA1 and RAD51.

The PALB2 protein acts as a hub, bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites. RAD51 plays a major role in homologous recombinational repair of DNA during double-strand break repair. In this process, an ATP-dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.

Clinical significance

The clinical phenotype of mutational defects in all Fanconi anemia (FA) complementation groups is similar. This phenotype is characterized by progressive bone marrow failure, cancer proneness and typical birth defects. The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks. The FA proteins interact through a multi-protein pathway. DNA interstrand crosslinks are highly deleterious damages that are repaired by homologous recombination involving coordination of FA proteins and breast cancer susceptibility gene 1 (BRCA1).

References

References

  1. "Entrez Gene: FANCL Fanconi anemia, complementation group L".
  2. (2017-01-19). "Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway". Molecular Cell.
  3. (Aug 2015). "The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL". Journal of Biological Chemistry.
  4. (May 2010). "Susceptibility pathways in Fanconi's anemia and breast cancer". The New England Journal of Medicine.
  5. (Sep 2009). "The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways". Journal of Biological Chemistry.
  6. (May 2011). "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair.
  7. (Feb 2011). "Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability". Clinical Cancer Research.
  8. (Oct 2002). "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood.
  9. (Aug 2014). "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". Biochimica et Biophysica Acta.
  10. (Jan 2013). "Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway". Molecular and Cellular Biology.
  11. (2014). "The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder". Annual Review of Biophysics.
  12. (2011-06-24). "DNA interstrand crosslink repair and cancer". Nature Reviews. Cancer.

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