FANCL

File:Homologous recombinational repair of DNA double-strand damage.jpg (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).{{cite journal |vauthors=D'Andrea AD |title=Susceptibility pathways in Fanconi's anemia and breast cancer |journal=N. Engl. J. Med. |volume=362 |issue=20 |pages=1909–19 |year=2010 |pmid=20484397 |pmc=3069698 |doi=10.1056/NEJMra0809889 }} The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI.{{cite journal |vauthors=Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME |title=The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways |journal=J. Biol. Chem. |volume=284 |issue=38 |pages=25560–8 |year=2009 |pmid=19633289 |pmc=2757957 |doi=10.1074/jbc.M109.007690 |doi-access=free }} ATM activates (phosphorylates) CHEK2 and FANCD2{{cite journal |vauthors=Castillo P, Bogliolo M, Surralles J |title=Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage |journal=DNA Repair (Amst.) |volume=10 |issue=5 |pages=518–25 |year=2011 |pmid=21466974 |doi=10.1016/j.dnarep.2011.02.007 }} CHEK2 phosphorylates BRCA1.{{cite journal |vauthors=Stolz A, Ertych N, Bastians H |title=Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability |journal=Clin. Cancer Res. |volume=17 |issue=3 |pages=401–5 |year=2011 |pmid=21088254 |doi=10.1158/1078-0432.CCR-10-1215 |doi-access=free }} Ubiquinated FANCD2 complexes with BRCA1 and RAD51.{{cite journal |vauthors=Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD |title=S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51 |journal=Blood |volume=100 |issue=7 |pages=2414–20 |year=2002 |pmid=12239151 |doi=10.1182/blood-2002-01-0278 |doi-access=free }} The PALB2 protein acts as a hub,{{cite journal |vauthors=Park JY, Zhang F, Andreassen PR |title=PALB2: the hub of a network of tumor suppressors involved in DNA damage responses |journal=Biochim. Biophys. Acta |volume=1846 |issue=1 |pages=263–75 |year=2014 |pmid=24998779 |pmc=4183126 |doi=10.1016/j.bbcan.2014.06.003 }} 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.{{cite journal |vauthors=Chun J, Buechelmaier ES, Powell SN |title=Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway |journal=Mol. Cell. Biol. |volume=33 |issue=2 |pages=387–95 |year=2013 |pmid=23149936 |pmc=3554112 |doi=10.1128/MCB.00465-12 }} 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.{{Cite journal|last1=Walden|first1=Helen|last2=Deans|first2=Andrew J.|date=2014|title=The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder|journal=Annual Review of Biophysics|volume=43|pages=257–278|doi=10.1146/annurev-biophys-051013-022737|issn=1936-1238|pmid=24773018}} The main cellular phenotype is hypersensitivity to DNA damage, particularly inter-strand DNA crosslinks.{{Cite journal|last1=Deans|first1=Andrew J.|last2=West|first2=Stephen C.|date=2011-06-24|title=DNA interstrand crosslink repair and cancer|journal=Nature Reviews. Cancer|volume=11|issue=7|pages=467–480|doi=10.1038/nrc3088|issn=1474-1768|pmc=3560328|pmid=21701511}} 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.{{Cite journal|last1=van Twest|first1=Sylvie|last2=Murphy|first2=Vincent J.|last3=Hodson|first3=Charlotte|last4=Tan|first4=Winnie|last5=Swuec|first5=Paolo|last6=O'Rourke|first6=Julienne J.|last7=Heierhorst|first7=Jörg|last8=Crismani|first8=Wayne|last9=Deans|first9=Andrew J.|date=2017-01-19|title=Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway|journal=Molecular Cell|volume=65|issue=2|pages=247–259|doi=10.1016/j.molcel.2016.11.005|issn=1097-4164|pmid=27986371|doi-access=free|hdl=2434/618936|hdl-access=free}} 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.{{cite journal |vauthors=Miles JA, Frost MG, Carroll E, Rowe ML, Howard MJ, Sidhu A, Chaugule VK, Alpi AF, Walden H |title=The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL |journal=J. Biol. Chem. |volume=290 |issue=34 |pages=20995–1006 |year=2015 |pmid=26149689 |pmc=4543658 |doi=10.1074/jbc.M115.675835 |doi-access=free }}

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).

{{reflist}}

{{refbegin | 2}}

• {{cite journal | vauthors=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1–2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=10.1016/0378-1119(94)90802-8 }}
• {{cite journal | vauthors=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library |journal=Gene |volume=200 |issue= 1–2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=10.1016/S0378-1119(97)00411-3 |display-authors=etal}}
• {{cite journal | vauthors=Agoulnik AI, Lu B, Zhu Q |title=A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd |journal=Hum. Mol. Genet. |volume=11 |issue= 24 |pages= 3047–53 |year= 2003 |pmid= 12417526 |doi=10.1093/hmg/11.24.3047 |display-authors=etal|doi-access=free }}
• {{cite journal | vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |bibcode=2002PNAS...9916899M |display-authors=etal|doi-access=free }}
• {{cite journal | vauthors=Lu B, Bishop CE |title=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=J. Biol. Chem. |volume=278 |issue= 18 |pages= 16289–96 |year= 2003 |pmid= 12574169 |doi= 10.1074/jbc.M211023200 |doi-access= free }}
• {{cite journal | vauthors=Lu B, Bishop CE |title=Late onset of spermatogenesis and gain of fertility in POG-deficient mice indicate that POG is not necessary for the proliferation of spermatogonia |journal=Biol. Reprod. |volume=69 |issue= 1 |pages= 161–8 |year= 2004 |pmid= 12606378 |doi= 10.1095/biolreprod.102.014654 |doi-access= free }}
• {{cite journal | vauthors=Meetei AR, Sechi S, Wallisch M |title=A Multiprotein Nuclear Complex Connects Fanconi Anemia and Bloom Syndrome |journal=Mol. Cell. Biol. |volume=23 |issue= 10 |pages= 3417–26 |year= 2003 |pmid= 12724401 |doi=10.1128/MCB.23.10.3417-3426.2003 | pmc=164758 |display-authors=etal}}
• {{cite journal | vauthors=Meetei AR, de Winter JP, Medhurst AL |title=A novel ubiquitin ligase is deficient in Fanconi anemia |journal=Nat. Genet. |volume=35 |issue= 2 |pages= 165–70 |year= 2003 |pmid= 12973351 |doi= 10.1038/ng1241 |s2cid=10149290 |display-authors=etal}}
• {{cite journal | vauthors=Ota T, Suzuki Y, Nishikawa T |title=Complete sequencing and characterization of 21,243 full-length human cDNAs |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 |display-authors=etal|doi-access=free }}
• {{cite journal | vauthors=Gerhard DS, Wagner L, Feingold EA |title=The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC) |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 | pmc=528928 |display-authors=etal}}
• {{cite journal | vauthors=Meetei AR, Levitus M, Xue Y |title=X-linked inheritance of Fanconi anemia complementation group B |journal=Nat. Genet. |volume=36 |issue= 11 |pages= 1219–24 |year= 2004 |pmid= 15502827 |doi= 10.1038/ng1458 |display-authors=etal|doi-access=free }}
• {{cite journal | vauthors=Hillier LW, Graves TA, Fulton RS |title=Generation and annotation of the DNA sequences of human chromosomes 2 and 4 |journal=Nature |volume=434 |issue= 7034 |pages= 724–31 |year= 2005 |pmid= 15815621 |doi= 10.1038/nature03466 |bibcode=2005Natur.434..724H |display-authors=etal|doi-access=free }}
• {{cite journal | vauthors=Meetei AR, Medhurst AL, Ling C |title=A Human Orthologue of Archaeal DNA Repair Protein Hef is Defective in Fanconi Anemia Complementation Group M |journal=Nat. Genet. |volume=37 |issue= 9 |pages= 958–63 |year= 2005 |pmid= 16116422 |doi= 10.1038/ng1626 | pmc=2704909 |display-authors=etal}}
• {{cite journal | vauthors=Gurtan AM, Stuckert P, D'Andrea AD |title=The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly |journal=J. Biol. Chem. |volume=281 |issue= 16 |pages= 10896–905 |year= 2006 |pmid= 16474167 |doi= 10.1074/jbc.M511411200 |doi-access= free }}
• {{cite journal | vauthors=Zhang J, Wang X, Lin CJ |title=Altered expression of FANCL confers mitomycin C sensitivity in Calu-6 lung cancer cells |journal=Cancer Biol. Ther. |volume=5 |issue= 12 |pages= 1632–6 |year= 2007 |pmid= 17106252 |doi= 10.4161/cbt.5.12.3351|display-authors=etal|doi-access=free }}

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{{Posttranslational modification}}