FANCL

E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.[4]

For Japanese cosmetics company, see FANCL Corporation.

FANCL
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3ZQS, 4CCG
Identifiers
Aliases	FANCL, FAAP43, PHF9, POG, Fanconi anemia complementation group L, FA complementation group L
External IDs	OMIM: 608111 MGI: 1914280 HomoloGene: 9987 GeneCards: FANCL
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p16.1 Start 58,159,243 bp[1] End 58,241,372 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • ubiquitin-protein transferase activity • GO:0001948 protein binding • metal ion binding • ubiquitin protein ligase binding • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity • transferase activity Cellular component • cytoplasm • cell nucleus • nuclear envelope • Fanconi anaemia nuclear complex • nucleoplasm • nuclear body • intracellular membrane-bounded organelle Biological process • protein ubiquitination • gamete generation • regulation of cell proliferation • interstrand cross-link repair • protein monoubiquitination • cellular response to DNA damage stimulus • DNA repair Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	55120	67030
Ensembl	ENSG00000115392	n/a
UniProt	Q9NW38	Q9CR14
RefSeq (mRNA)	NM_001114636 NM_018062 NM_001374615	NM_001277273 NM_025923
RefSeq (protein)	NP_001108108 NP_060532 NP_001361544	NP_001264202 NP_080199
Location (UCSC)	Chr 2: 58.16 – 58.24 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Function

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).[5] The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI.[6] ATM activates (phosphorylates) CHEK2 and FANCD2[7] CHEK2 phosphorylates BRCA1.[8] Ubiquinated FANCD2 complexes with BRCA1 and RAD51.[9] The PALB2 protein acts as a hub,[10] 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.[11] 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.

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.[12] The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks.[13] 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.[14] 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.[15]

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.[5] 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

1. GRCh38: Ensembl release 89: ENSG00000115392 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Entrez Gene: FANCL Fanconi anemia, complementation group L".
5. D'Andrea AD (2010). "Susceptibility pathways in Fanconi's anemia and breast cancer". N. Engl. J. Med. 362 (20): 1909–19. doi:10.1056/NEJMra0809889. PMC 3069698. PMID 20484397.
6. Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME (2009). "The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways". J. Biol. Chem. 284 (38): 25560–8. doi:10.1074/jbc.M109.007690. PMC 2757957. PMID 19633289.
7. Castillo P, Bogliolo M, Surralles J (2011). "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair (Amst.). 10 (5): 518–25. doi:10.1016/j.dnarep.2011.02.007. PMID 21466974.
8. Stolz A, Ertych N, Bastians H (2011). "Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability". Clin. Cancer Res. 17 (3): 401–5. doi:10.1158/1078-0432.CCR-10-1215. PMID 21088254.
9. Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD (2002). "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood. 100 (7): 2414–20. doi:10.1182/blood-2002-01-0278. PMID 12239151.
10. Park JY, Zhang F, Andreassen PR (2014). "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". Biochim. Biophys. Acta. 1846 (1): 263–75. doi:10.1016/j.bbcan.2014.06.003. PMC 4183126. PMID 24998779.
11. Chun J, Buechelmaier ES, Powell SN (2013). "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. doi:10.1128/MCB.00465-12. PMC 3554112. PMID 23149936.
12. 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.
13. 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. PMC 3560328. PMID 21701511.
14. 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. doi:10.1016/j.molcel.2016.11.005. ISSN 1097-4164. PMID 27986371.
15. Miles JA, Frost MG, Carroll E, Rowe ML, Howard MJ, Sidhu A, Chaugule VK, Alpi AF, Walden H (2015). "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. doi:10.1074/jbc.M115.675835. PMC 4543658. PMID 26149689.

Further reading

• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Agoulnik AI, Lu B, Zhu Q, et al. (2003). "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. doi:10.1093/hmg/11.24.3047. PMID 12417526.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "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. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Lu B, Bishop CE (2003). "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. doi:10.1074/jbc.M211023200. PMID 12574169.
• Lu B, Bishop CE (2004). "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. doi:10.1095/biolreprod.102.014654. PMID 12606378.
• Meetei AR, Sechi S, Wallisch M, et al. (2003). "A Multiprotein Nuclear Complex Connects Fanconi Anemia and Bloom Syndrome". Mol. Cell. Biol. 23 (10): 3417–26. doi:10.1128/MCB.23.10.3417-3426.2003. PMC 164758. PMID 12724401.
• Meetei AR, de Winter JP, Medhurst AL, et al. (2003). "A novel ubiquitin ligase is deficient in Fanconi anemia". Nat. Genet. 35 (2): 165–70. doi:10.1038/ng1241. PMID 12973351.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Meetei AR, Levitus M, Xue Y, et al. (2004). "X-linked inheritance of Fanconi anemia complementation group B". Nat. Genet. 36 (11): 1219–24. doi:10.1038/ng1458. PMID 15502827.
• Hillier LW, Graves TA, Fulton RS, et al. (2005). "Generation and annotation of the DNA sequences of human chromosomes 2 and 4". Nature. 434 (7034): 724–31. doi:10.1038/nature03466. PMID 15815621.
• Meetei AR, Medhurst AL, Ling C, et al. (2005). "A Human Orthologue of Archaeal DNA Repair Protein Hef is Defective in Fanconi Anemia Complementation Group M". Nat. Genet. 37 (9): 958–63. doi:10.1038/ng1626. PMC 2704909. PMID 16116422.
• Gurtan AM, Stuckert P, D'Andrea AD (2006). "The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly". J. Biol. Chem. 281 (16): 10896–905. doi:10.1074/jbc.M511411200. PMID 16474167.
• Zhang J, Wang X, Lin CJ, et al. (2007). "Altered expression of FANCL confers mitomycin C sensitivity in Calu-6 lung cancer cells". Cancer Biol. Ther. 5 (12): 1632–6. doi:10.4161/cbt.5.12.3351. PMID 17106252.