FANCL explained

E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.^[1]

Function

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.^[2] The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks.^[3] 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.^[4] The ELF domain of FANCL is also required to mediate a non-covalent interactionbetween 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.^[5]

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. 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).

Further reading

• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 . etal.
• Agoulnik AI, Lu B, Zhu Q . A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd . Hum. Mol. Genet. . 11 . 24 . 3047–53 . 2003 . 12417526 . 10.1093/hmg/11.24.3047 . etal. free .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .
• Lu B, Bishop CE . Mouse GGN1 and GGN3, two germ cell-specific proteins from the single gene Ggn, interact with mouse POG and play a role in spermatogenesis . J. Biol. Chem. . 278 . 18 . 16289–96 . 2003 . 12574169 . 10.1074/jbc.M211023200 . free .
• Lu B, Bishop CE . Late onset of spermatogenesis and gain of fertility in POG-deficient mice indicate that POG is not necessary for the proliferation of spermatogonia . Biol. Reprod. . 69 . 1 . 161–8 . 2004 . 12606378 . 10.1095/biolreprod.102.014654 . free .
• Meetei AR, Sechi S, Wallisch M . A Multiprotein Nuclear Complex Connects Fanconi Anemia and Bloom Syndrome . Mol. Cell. Biol. . 23 . 10 . 3417–26 . 2003 . 12724401 . 10.1128/MCB.23.10.3417-3426.2003 . 164758 . etal.
• Meetei AR, de Winter JP, Medhurst AL . A novel ubiquitin ligase is deficient in Fanconi anemia . Nat. Genet. . 35 . 2 . 165–70 . 2003 . 12973351 . 10.1038/ng1241 . 10149290 . etal.
• Ota T, Suzuki Y, Nishikawa T . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . etal. free .
• Gerhard DS, Wagner L, Feingold EA . The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . etal.
• Meetei AR, Levitus M, Xue Y . X-linked inheritance of Fanconi anemia complementation group B . Nat. Genet. . 36 . 11 . 1219–24 . 2004 . 15502827 . 10.1038/ng1458 . etal. free .
• Hillier LW, Graves TA, Fulton RS . Generation and annotation of the DNA sequences of human chromosomes 2 and 4 . Nature . 434 . 7034 . 724–31 . 2005 . 15815621 . 10.1038/nature03466 . 2005Natur.434..724H . etal. free .
• Meetei AR, Medhurst AL, Ling C . A Human Orthologue of Archaeal DNA Repair Protein Hef is Defective in Fanconi Anemia Complementation Group M . Nat. Genet. . 37 . 9 . 958–63 . 2005 . 16116422 . 10.1038/ng1626 . 2704909 . etal.
• Gurtan AM, Stuckert P, D'Andrea AD . The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly . J. Biol. Chem. . 281 . 16 . 10896–905 . 2006 . 16474167 . 10.1074/jbc.M511411200 . free .
• Zhang J, Wang X, Lin CJ . Altered expression of FANCL confers mitomycin C sensitivity in Calu-6 lung cancer cells . Cancer Biol. Ther. . 5 . 12 . 1632–6 . 2007 . 17106252 . 10.4161/cbt.5.12.3351. etal. free .

Notes and References

1. Web site: Entrez Gene: FANCL Fanconi anemia, complementation group L.
2. Walden. Helen. Deans. Andrew J.. 2014. The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder. Annual Review of Biophysics. 43. 257–278. 10.1146/annurev-biophys-051013-022737. 1936-1238. 24773018.
3. Deans. Andrew J.. West. Stephen C.. 2011-06-24. DNA interstrand crosslink repair and cancer. Nature Reviews. Cancer. 11. 7. 467–480. 10.1038/nrc3088. 1474-1768. 3560328. 21701511.
4. van Twest. Sylvie. Murphy. Vincent J.. Hodson. Charlotte. Tan. Winnie. Swuec. Paolo. O'Rourke. Julienne J.. Heierhorst. Jörg. Crismani. Wayne. Deans. Andrew J.. 2017-01-19. Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway. Molecular Cell. 65. 2. 247–259. 10.1016/j.molcel.2016.11.005. 1097-4164. 27986371. free. 2434/618936. free.
5. Miles JA, Frost MG, Carroll E, Rowe ML, Howard MJ, Sidhu A, Chaugule VK, Alpi AF, Walden H . The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL . J. Biol. Chem. . 290 . 34 . 20995–1006 . 2015 . 26149689 . 4543658 . 10.1074/jbc.M115.675835 . free .