FANCL

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; OMA:FANCL - orthologs
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2p16.1 Start 58,159,243 bp [1] End 58,241,410 bp [1]
Gene location (Mouse) Chr. Chromosome 11 (mouse) [2] Band 11|11 A3.3 Start 26,336,135 bp [2] End 26,421,876 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in pituitary gland anterior pituitary Achilles tendon right adrenal cortex corpus callosum left adrenal cortex C1 segment tibia secondary oocyte right uterine tube Top expressed in Paneth cell primitive streak abdominal wall mandibular prominence fetal liver hematopoietic progenitor cell epiblast endocardial cushion maxillary prominence interventricular septum fossa More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ubiquitin-protein transferase activity protein binding metal ion binding ubiquitin protein ligase binding ubiquitin protein ligase activity transferase activity Cellular component cytoplasm nucleus nuclear envelope Fanconi anaemia nuclear complex nucleoplasm nuclear body intracellular membrane-bounded organelle Biological process protein ubiquitination gamete generation regulation of cell population 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 ENSMUSG00000004018 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 Chr 11: 26.34 – 26.42 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene. ^[5]

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. ^[6] 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. ^[7]

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. ^[8] 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

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). ^[8] The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI. ^[9] ATM activates (phosphorylates) CHEK2 and FANCD2. ^[10] CHEK2 phosphorylates BRCA1. ^[11] Ubiquitinated FANCD2 complexes with BRCA1 and RAD51. ^[12]

The PALB2 protein acts as a hub, ^[13] 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. ^[14] 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. ^[15] The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks. ^[16] 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

1. GRCh38: Ensembl release 89: ENSG00000115392 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000004018 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: FANCL Fanconi anemia, complementation group L".
6. van Twest S, Murphy VJ, Hodson C, Tan W, Swuec P, O'Rourke JJ, 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 . hdl: 2434/618936 . ISSN   1097-4164. PMID   27986371.
7. Miles JA, Frost MG, Carroll E, Rowe ML, Howard MJ, Sidhu A, et al. (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. 290 (34): 20995–21006. doi: 10.1074/jbc.M115.675835 . PMC   4543658 . PMID   26149689.
8. D'Andrea AD (May 2010). "Susceptibility pathways in Fanconi's anemia and breast cancer". The New England Journal of Medicine. 362 (20): 1909–1919. doi:10.1056/NEJMra0809889. PMC   3069698 . PMID   20484397.
9. Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME (Sep 2009). "The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways". Journal of Biological Chemistry. 284 (38): 25560–25568. doi: 10.1074/jbc.M109.007690 . PMC   2757957 . PMID   19633289.
10. Castillo P, Bogliolo M, Surralles J (May 2011). "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair. 10 (5): 518–525. doi:10.1016/j.dnarep.2011.02.007. PMID   21466974.
11. Stolz A, Ertych N, Bastians H (Feb 2011). "Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability". Clinical Cancer Research. 17 (3): 401–405. doi: 10.1158/1078-0432.CCR-10-1215 . PMID   21088254.
12. Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD (Oct 2002). "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood. 100 (7): 2414–2420. doi: 10.1182/blood-2002-01-0278 . PMID   12239151.
13. Park JY, Zhang F, Andreassen PR (Aug 2014). "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". Biochimica et Biophysica Acta. 1846 (1): 263–275. doi:10.1016/j.bbcan.2014.06.003. PMC   4183126 . PMID   24998779.
14. Chun J, Buechelmaier ES, Powell SN (Jan 2013). "Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway". Molecular and Cellular Biology. 33 (2): 387–395. doi:10.1128/MCB.00465-12. PMC   3554112 . PMID   23149936.
15. Walden H, Deans AJ (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.
16. Deans AJ, West SC (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.

Further reading

• Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID   8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID   9373149.
• Agoulnik AI, Lu B, Zhu Q, Truong C, Ty MT, Arango N, et al. (Nov 2002). "A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd". Human Molecular Genetics. 11 (24): 3047–3053. doi: 10.1093/hmg/11.24.3047 . PMID   12417526.
• Lu B, Bishop CE (May 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". Journal of Biological Chemistry. 278 (18): 16289–16296. doi: 10.1074/jbc.M211023200 . PMID   12574169.
• Lu B, Bishop CE (Jul 2003). "Late onset of spermatogenesis and gain of fertility in POG-deficient mice indicate that POG is not necessary for the proliferation of spermatogonia". Biology of Reproduction. 69 (1): 161–168. doi: 10.1095/biolreprod.102.014654 . PMID   12606378.
• Meetei AR, Sechi S, Wallisch M, Yang D, Young MK, Joenje H, et al. (May 2003). "A Multiprotein Nuclear Complex Connects Fanconi Anemia and Bloom Syndrome". Molecular and Cellular Biology. 23 (10): 3417–3426. doi:10.1128/MCB.23.10.3417-3426.2003. PMC   164758 . PMID   12724401.
• Meetei AR, Winter JP, Medhurst AL, Wallisch M, Waisfisz Q, Vrugt HJ, et al. (Oct 2003). "A novel ubiquitin ligase is deficient in Fanconi anemia". Nature Genetics. 35 (2): 165–170. doi:10.1038/ng1241. PMID   12973351. S2CID   10149290.
• Meetei AR, Levitus M, Xue Y, Medhurst AL, Zwaan M, Ling C, et al. (Nov 2004). "X-linked inheritance of Fanconi anemia complementation group B". Nature Genetics. 36 (11): 1219–1224. doi: 10.1038/ng1458 . PMID   15502827.
• Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, et al. (Sep 2005). "A Human Orthologue of Archaeal DNA Repair Protein Hef is Defective in Fanconi Anemia Complementation Group M". Nature Genetics. 37 (9): 958–963. doi:10.1038/ng1626. PMC   2704909 . PMID   16116422.
• Gurtan AM, Stuckert P, D'Andrea AD (Apr 2006). "The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly". Journal of Biological Chemistry. 281 (16): 10896–10905. doi: 10.1074/jbc.M511411200 . PMID   16474167.
• Zhang J, Wang X, Lin CJ, Couch FJ, Fei P (Dec 2006). "Altered expression of FANCL confers mitomycin C sensitivity in Calu-6 lung cancer cells". Cancer Biology & Therapy. 5 (12): 1632–1636. doi: 10.4161/cbt.5.12.3351 . PMID   17106252.