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Protein-coding gene in the species Homo sapiens From Wikipedia, the free encyclopedia
E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.[5]
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Aliases | FANCL, FAAP43, PHF9, POG, Fanconi anemia complementation group L, FA complementation group L | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 608111; MGI: 1914280; HomoloGene: 9987; GeneCards: FANCL; OMA:FANCL - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.[13] The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks.[14] 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).
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 3 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.[15] The ELF domain of FANCL is also required to mediate a non-covalent interaction between FANCL and ubiquitin. The ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of FANCB and ubiquitin binding by FANCL in vivo.[16]
A nuclear complex containing FANCL (as well as FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCM) is essential for the activation of the FANCD2 protein to the mono-ubiquitinated isoform.[6] In normal, non-mutant, cells FANCD2 is mono-ubiquinated in response to DNA damage. Activated FANCD2 protein co-localizes with BRCA1 (breast cancer susceptibility protein) at ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes (see Figure: Recombinational repair of double strand damage).
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