FANCD2

{{Short description|Protein-coding gene in the species Homo sapiens}}

Fanconi anemia group D2 protein is a protein that in humans is encoded by the FANCD2 gene.{{cite journal | vauthors = Whitney M, Thayer M, Reifsteck C, Olson S, Smith L, Jakobs PM, Leach R, Naylor S, Joenje H, Grompe M | display-authors = 6 | title = Microcell mediated chromosome transfer maps the Fanconi anaemia group D gene to chromosome 3p | journal = Nature Genetics | volume = 11 | issue = 3 | pages = 341–3 | date = November 1995 | pmid = 7581463 | doi = 10.1038/ng1195-341 | s2cid = 451042 }}{{cite journal | vauthors = Timmers C, Taniguchi T, Hejna J, Reifsteck C, Lucas L, Bruun D, Thayer M, Cox B, Olson S, D'Andrea AD, Moses R, Grompe M | display-authors = 6 | title = Positional cloning of a novel Fanconi anemia gene, FANCD2 | journal = Molecular Cell | volume = 7 | issue = 2 | pages = 241–8 | date = February 2001 | pmid = 11239453 | doi = 10.1016/S1097-2765(01)00172-1 | doi-access = free }} The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2 (this gene), FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN, FANCO, FANCP, FANCQ, FANCR, FANCS, FANCT, FANCU, FANCV, and probably FANCW. Fanconi anemia proteins, including FANCD2, are an emerging therapeutic target in cancer {{Cite journal |last=Sharp |first=Michael F. |last2=Bythell-Douglas |first2=Rohan |last3=Deans |first3=Andrew J. |last4=Crismani |first4=Wayne |date=2021 |title=The Fanconi anemia ubiquitin E3 ligase complex as an anti-cancer target |url=https://linkinghub.elsevier.com/retrieve/pii/S1097276521003282 |journal=Molecular Cell |language=en |volume=81 |issue=11 |pages=2278–2289 |doi=10.1016/j.molcel.2021.04.023}}

Function

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 = The New England Journal of Medicine | volume = 362 | issue = 20 | pages = 1909–19 | date = May 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 = The Journal of Biological Chemistry | volume = 284 | issue = 38 | pages = 25560–8 | date = September 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 | volume = 10 | issue = 5 | pages = 518–25 | date = May 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 = Clinical Cancer Research | volume = 17 | issue = 3 | pages = 401–5 | date = February 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 | date = October 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 = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1846 | issue = 1 | pages = 263–75 | date = August 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 = Molecular and Cellular Biology | volume = 33 | issue = 2 | pages = 387–95 | date = January 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.]]

Fanconi anemia is a disorder with a recessive Mendelian pattern of inheritance characterized by chromosomal instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group D2. This protein is monoubiquitinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins (BRCA1 and BRCA2) involved in homology-directed DNA repair (see Figure: Recombinational repair of DNA double-strand damages). A nuclear complex containing FANCA, [Fanconi anemia, complementation group A], FANCB, FANCC, FANCE, FANCF, FANCL and FANCG proteins is required for the activation of the FANCD2 protein to the mono-ubiquitinated isoform.{{cite journal | vauthors = Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D'Andrea AD | display-authors = 6 | title = Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway | journal = Molecular Cell | volume = 7 | issue = 2 | pages = 249–62 | date = February 2001 | pmid = 11239454 | doi = 10.1016/s1097-2765(01)00173-3 | doi-access = free }}

Mono-ubiquination of FANCD2 is essential for repairing DNA interstrand crosslinks, and clamps the protein on DNA together with its partner protein FANCI. The monoubiquitinated FANCD2:FANCI complex coats DNA in a filament-like array, potentially as a way to protect DNA associated with stalled replication.{{cite journal | vauthors = Tan W, van Twest S, Leis A, Bythell-Douglas R, Murphy VJ, Sharp M, Parker MW, Crismani W, Deans AJ | display-authors = 6 | title = Monoubiquitination by the human Fanconi anemia core complex clamps FANCI:FANCD2 on DNA in filamentous arrays | journal = eLife | volume = 9 | date = March 2020 | pmid = 32167469 | doi = 10.7554/eLife.54128 | pmc = 7156235 | doi-access = free }}

Mono-ubiquitination is also required for interaction with the nuclease FAN1. FAN1 recruitment and its consequent activity restrain DNA replication fork progression and prevent chromosome abnormalities from occurring when DNA replication forks stall.{{cite journal | vauthors = Lachaud C, Moreno A, Marchesi F, Toth R, Blow JJ, Rouse J | title = Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability | journal = Science | volume = 351 | issue = 6275 | pages = 846–9 | date = February 2016 | pmid = 26797144 | pmc = 4770513 | doi = 10.1126/science.aad5634 | bibcode = 2016Sci...351..846L }}

Infertility

Humans with a FANCD deficiency display hypogonadism, male infertility, impaired spermatogenesis, and reduced female fertility. Similarly, mice deficient in FANCD2 show hypogonadism, impaired fertility and impaired gametogenesis.{{cite journal | vauthors = Parmar K, D'Andrea A, Niedernhofer LJ | title = Mouse models of Fanconi anemia | journal = Mutation Research | volume = 668 | issue = 1–2 | pages = 133–40 | date = July 2009 | pmid = 19427003 | pmc = 2778466 | doi = 10.1016/j.mrfmmm.2009.03.015 }}

In the non-mutant mouse, FANCD2 is expressed in spermatogonia, pre-leptotene spermatocytes, and in spermatocytes in the leptotene, zygotene and early pachytene stages of meiosis.{{cite journal | vauthors = Jamsai D, O'Connor AE, O'Donnell L, Lo JC, O'Bryan MK | title = Uncoupling of transcription and translation of Fanconi anemia (FANC) complex proteins during spermatogenesis | journal = Spermatogenesis | volume = 5 | issue = 1 | pages = e979061 | year = 2015 | pmid = 26413409 | pmc = 4581071 | doi = 10.4161/21565562.2014.979061 }} In synaptonemal complexes of meiotic chromosomes, activated FANCD2 protein co-localizes with BRCA1 (breast cancer susceptibility protein). FANCD2 mutant mice exhibit chromosome mis-pairing during the pachytene stage of meiosis and germ cell loss.{{cite journal | vauthors = Houghtaling S, Timmers C, Noll M, Finegold MJ, Jones SN, Meyn MS, Grompe M | title = Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice | journal = Genes & Development | volume = 17 | issue = 16 | pages = 2021–35 | date = August 2003 | pmid = 12893777 | pmc = 196256 | doi = 10.1101/gad.1103403 }} Activated FANCD2 protein may normally function prior to the initiation of meiotic recombination, perhaps to prepare chromosomes for synapsis, or to regulate subsequent recombination events.

Clinical significance

Tobacco smoke suppresses the expression of FANCD2, which codes for a DNA damage "caretaker" or repair mechanism.{{cite journal | vauthors = Hays LE, Zodrow DM, Yates JE, Deffebach ME, Jacoby DB, Olson SB, Pankow JF, Bagby GC | title = Cigarette smoke induces genetic instability in airway epithelial cells by suppressing FANCD2 expression | journal = British Journal of Cancer | volume = 98 | issue = 10 | pages = 1653–61 | date = May 2008 | pmid = 18475298 | pmc = 2391131 | doi = 10.1038/sj.bjc.6604362 }}

=Cancer=

FANCD2 mutant mice have a significantly increased incidence of tumors including ovarian, gastric and hepatic adenomas as well as hepatocellular, lung, ovarian and mammary carcinomas. Humans with a FANCD2 deficiency have increased acute myeloid leukemia, and squamous cell carcinomas (head and neck squamous cell carcinomas and anogenital carcinomas). Lung squamous tumors express high levels of FANCD2 and members of Fanconia anemia pathway.{{Cite bioRxiv|last1=Prieto-Garcia |first1=C. |last2=Hartmann |first2=O |last3=Diefenbacher |first3=M. |last4=et |first4=al. |date=Sep 2020 |title=Inhibition of USP28 overcomes Cisplatin-Resistance of Squamous Tumors by Suppression of the Fanconi Anemia Pathway |biorxiv=10.1101/2020.09.10.291278 }}

FANCD2 monoubiquitination is also a potential therapeutic target in the treatment of cancer.{{cite journal | vauthors = Sharp MF, Murphy VJ, Twest SV, Tan W, Lui J, Simpson KJ, Deans AJ, Crismani W | display-authors = 6 | title = Methodology for the identification of small molecule inhibitors of the Fanconi Anaemia ubiquitin E3 ligase complex | journal = Scientific Reports | volume = 10 | issue = 1 | pages = 7959 | date = May 2020 | pmid = 32409752 | doi = 10.1038/s41598-020-64868-7 | pmc = 7224301 | bibcode = 2020NatSR..10.7959S }}

Interactions

FANCD2 has been shown to interact with:

FANCI{{cite journal | vauthors = Yuan F, El Hokayem J, Zhou W, Zhang Y | title = FANCI protein binds to DNA and interacts with FANCD2 to recognize branched structures | journal = The Journal of Biological Chemistry | volume = 284 | issue = 36 | pages = 24443–52 | date = September 2009 | pmid = 19561358 | pmc = 2782037 | doi = 10.1074/jbc.m109.016006 | doi-access = free }}{{cite journal | vauthors = Joo W, Xu G, Persky NS, Smogorzewska A, Rudge DG, Buzovetsky O, Elledge SJ, Pavletich NP | display-authors = 6 | title = Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway | journal = Science | volume = 333 | issue = 6040 | pages = 312–6 | date = July 2011 | pmid = 21764741 | pmc = 3310437 | doi = 10.1126/science.1205805 | bibcode = 2011Sci...333..312J }}
Ataxia telangiectasia mutated,{{cite journal | vauthors = Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST, Lane WS, Kastan MB, D'Andrea AD | display-authors = 6 | title = Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways | journal = Cell | volume = 109 | issue = 4 | pages = 459–72 | date = May 2002 | pmid = 12086603 | doi = 10.1016/S0092-8674(02)00747-X | s2cid = 16580666 | doi-access = free }}{{cite journal | vauthors = Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H, Gross HJ, Joenje H, Hoatlin ME, Mathew CG, Huber PA | display-authors = 6 | title = Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport | journal = Experimental Cell Research | volume = 289 | issue = 2 | pages = 211–21 | date = October 2003 | pmid = 14499622 | doi = 10.1016/S0014-4827(03)00261-1 }}
BARD1,{{cite journal | vauthors = Vandenberg CJ, Gergely F, Ong CY, Pace P, Mallery DL, Hiom K, Patel KJ | title = BRCA1-independent ubiquitination of FANCD2 | journal = Molecular Cell | volume = 12 | issue = 1 | pages = 247–54 | date = July 2003 | pmid = 12887909 | doi = 10.1016/S1097-2765(03)00281-8 | doi-access = free }}
BRCA1.
BRCA2,{{cite journal | vauthors = Wang X, Andreassen PR, D'Andrea AD | title = Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin | journal = Molecular and Cellular Biology | volume = 24 | issue = 13 | pages = 5850–62 | date = July 2004 | pmid = 15199141 | pmc = 480901 | doi = 10.1128/MCB.24.13.5850-5862.2004 }}
FANCE,{{cite journal | vauthors = Hussain S, Wilson JB, Medhurst AL, Hejna J, Witt E, Ananth S, Davies A, Masson JY, Moses R, West SC, de Winter JP, Ashworth A, Jones NJ, Mathew CG | display-authors = 6 | title = Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways | journal = Human Molecular Genetics | volume = 13 | issue = 12 | pages = 1241–8 | date = June 2004 | pmid = 15115758 | doi = 10.1093/hmg/ddh135 | doi-access = free }}{{cite journal | vauthors = Gordon SM, Buchwald M | title = Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems | journal = Blood | volume = 102 | issue = 1 | pages = 136–41 | date = July 2003 | pmid = 12649160 | doi = 10.1182/blood-2002-11-3517 }}{{cite journal | vauthors = Pace P, Johnson M, Tan WM, Mosedale G, Sng C, Hoatlin M, de Winter J, Joenje H, Gergely F, Patel KJ | display-authors = 6 | title = FANCE: the link between Fanconi anaemia complex assembly and activity | journal = The EMBO Journal | volume = 21 | issue = 13 | pages = 3414–23 | date = July 2002 | pmid = 12093742 | pmc = 125396 | doi = 10.1093/emboj/cdf355 }}
HTATIP,{{cite journal | vauthors = Hejna J, Holtorf M, Hines J, Mathewson L, Hemphill A, Al-Dhalimy M, Olson SB, Moses RE | display-authors = 6 | title = Tip60 is required for DNA interstrand cross-link repair in the Fanconi anemia pathway | journal = The Journal of Biological Chemistry | volume = 283 | issue = 15 | pages = 9844–51 | date = April 2008 | pmid = 18263878 | pmc = 2398728 | doi = 10.1074/jbc.M709076200 | doi-access = free }} and
MEN1.{{cite journal | vauthors = Jin S, Mao H, Schnepp RW, Sykes SM, Silva AC, D'Andrea AD, Hua X | title = Menin associates with FANCD2, a protein involved in repair of DNA damage | journal = Cancer Research | volume = 63 | issue = 14 | pages = 4204–10 | date = July 2003 | pmid = 12874027 }}

FANCD2

Function

Infertility

Clinical significance

=Cancer=

Interactions

References

External links

Further reading