Biology:FANCL
![]() Generic protein structure example |
E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.[1]
Function
![](/wiki/images/thumb/d/dc/Homologous_recombinational_repair_of_DNA_double-strand_damage.jpg/300px-Homologous_recombinational_repair_of_DNA_double-strand_damage.jpg)
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.[9] The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks.[10] 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.[11] 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.[12]
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.[2] 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).
References
- ↑ "Entrez Gene: FANCL Fanconi anemia, complementation group L". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=55120.
- ↑ 2.0 2.1 "Susceptibility pathways in Fanconi's anemia and breast cancer". N. Engl. J. Med. 362 (20): 1909–19. 2010. doi:10.1056/NEJMra0809889. PMID 20484397.
- ↑ "The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways". J. Biol. Chem. 284 (38): 25560–8. 2009. doi:10.1074/jbc.M109.007690. PMID 19633289.
- ↑ "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair (Amst.) 10 (5): 518–25. 2011. doi:10.1016/j.dnarep.2011.02.007. PMID 21466974.
- ↑ "Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability". Clin. Cancer Res. 17 (3): 401–5. 2011. doi:10.1158/1078-0432.CCR-10-1215. PMID 21088254.
- ↑ "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood 100 (7): 2414–20. 2002. doi:10.1182/blood-2002-01-0278. PMID 12239151.
- ↑ "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". Biochim. Biophys. Acta 1846 (1): 263–75. 2014. doi:10.1016/j.bbcan.2014.06.003. PMID 24998779.
- ↑ "Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway". Mol. Cell. Biol. 33 (2): 387–95. 2013. doi:10.1128/MCB.00465-12. PMID 23149936.
- ↑ 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. doi:10.1146/annurev-biophys-051013-022737. ISSN 1936-1238. PMID 24773018.
- ↑ Deans, Andrew J.; West, Stephen C. (2011-06-24). "DNA interstrand crosslink repair and cancer". Nature Reviews. Cancer 11 (7): 467–480. doi:10.1038/nrc3088. ISSN 1474-1768. PMID 21701511.
- ↑ van Twest, Sylvie; Murphy, Vincent J.; Hodson, Charlotte; Tan, Winnie; Swuec, Paolo; O'Rourke, Julienne J.; Heierhorst, Jörg; Crismani, Wayne et al. (2017-01-19). "Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway". Molecular Cell 65 (2): 247–259. doi:10.1016/j.molcel.2016.11.005. ISSN 1097-4164. PMID 27986371.
- ↑ "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. doi:10.1074/jbc.M115.675835. PMID 26149689.
Further reading
- "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.". Gene 138 (1–2): 171–4. 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- "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. doi:10.1093/hmg/11.24.3047. PMID 12417526.
- "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. doi:10.1073/pnas.242603899. PMID 12477932. Bibcode: 2002PNAS...9916899M.
- "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. doi:10.1074/jbc.M211023200. PMID 12574169.
- "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. doi:10.1095/biolreprod.102.014654. PMID 12606378.
- "A Multiprotein Nuclear Complex Connects Fanconi Anemia and Bloom Syndrome". Mol. Cell. Biol. 23 (10): 3417–26. 2003. doi:10.1128/MCB.23.10.3417-3426.2003. PMID 12724401.
- "A novel ubiquitin ligase is deficient in Fanconi anemia". Nat. Genet. 35 (2): 165–70. 2003. doi:10.1038/ng1241. PMID 12973351.
- "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. 2004. doi:10.1038/ng1285. PMID 14702039.
- "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. 2004. doi:10.1101/gr.2596504. PMID 15489334.
- "X-linked inheritance of Fanconi anemia complementation group B". Nat. Genet. 36 (11): 1219–24. 2004. doi:10.1038/ng1458. PMID 15502827.
- "Generation and annotation of the DNA sequences of human chromosomes 2 and 4". Nature 434 (7034): 724–31. 2005. doi:10.1038/nature03466. PMID 15815621. Bibcode: 2005Natur.434..724H.
- "A Human Orthologue of Archaeal DNA Repair Protein Hef is Defective in Fanconi Anemia Complementation Group M". Nat. Genet. 37 (9): 958–63. 2005. doi:10.1038/ng1626. PMID 16116422.
- "The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly". J. Biol. Chem. 281 (16): 10896–905. 2006. doi:10.1074/jbc.M511411200. PMID 16474167.
- "Altered expression of FANCL confers mitomycin C sensitivity in Calu-6 lung cancer cells". Cancer Biol. Ther. 5 (12): 1632–6. 2007. doi:10.4161/cbt.5.12.3351. PMID 17106252.