Biology:FANCD2

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Fanconi anemia group D2 protein (FANCD2) is a nuclear protein that in humans is encoded by the FANCD2 gene that plays a central role in the Fanconi anemia (FA)/BRCA pathway, which safeguards genome stability by coordinating the repair of DNA interstrand crosslinks and other DNA replication‑blocking lesions. In response to DNA damage or S phase progression, FANCD2 is activated by ubiquitination by the FA core complex and forms a heterodimeric complex with FANCI. This complex localizes to chromatin foci together with BRCA1 and other DNA repair factors, where it helps orchestrate nucleolytic processing and downstream repair events.[1][2][3]

Germline loss‑of‑function mutations in FANCD2 cause the FA complementation group D2 subtype, characterized by bone marrow failure, congenital abnormalities, chromosomal instability and markedly increased risk of hematologic and solid malignancies. Dysregulated FANCD2 expression and activity have also been implicated in the development and progression of sporadic cancers.

Fanconi anemia proteins, including FANCD2, are an emerging therapeutic target in cancer [4]

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.

This gene encodes the Fanconi anemia complementation group D2 protein (FANCD2), a central component of the Fanconi anemia DNA repair pathway. FANCD2 is monoubiquitinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins including BRCA1 and BRCA2 involved in homology-directed DNA repair.[12] A nuclear complex containing FANCA, FANCB, FANCC, FANCE, FANCF, FANCL, and FANCG proteins is required for activation of FANCD2 to the mono-ubiquitinated isoform.[12]

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 protecting DNA associated with stalled replication forks.[13]

Mono-ubiquitination is also required for interaction with the nuclease FAN1. Recruitment of FAN1 by ubiquitinated FANCD2 restrains DNA replication fork progression and helps prevent chromosome abnormalities when replication forks stall.[14]

Clinical significance

Fanconi anemia

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. Mutations in FANCD2 cause Fanconi anemia complementation group D2. The members of the Fanconi anemia complementation group do not share sequence similarity, but are related through their assembly into a common nuclear protein complex involved in DNA repair.[12]

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.[15][16] Humans with a FANCD2 deficiency have increased acute myeloid leukemia, and squamous cell carcinomas (head and neck squamous cell carcinomas and anogenital carcinomas).[15] Lung squamous tumors express high levels of FANCD2 and members of Fanconia anemia pathway.[17]

FANCD2 monoubiquitination is also a potential therapeutic target in the treatment of cancer.[18]

Smoking

Tobacco smoke suppresses the expression of FANCD2, which codes for a DNA damage "caretaker" or repair mechanism.[19]

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.[15]

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.[20] In synaptonemal complexes of meiotic chromosomes, activated FANCD2 protein co-localizes with BRCA1 (breast cancer susceptibility protein).[12] FANCD2 mutant mice exhibit chromosome mis-pairing during the pachytene stage of meiosis and germ cell loss.[16] 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.[12]

Interactions

FANCD2 has been shown to interact with:

References

  1. ↑ "Microcell mediated chromosome transfer maps the Fanconi anaemia group D gene to chromosome 3p". Nature Genetics 11 (3): 341–343. November 1995. doi:10.1038/ng1195-341. PMID 7581463. 
  2. ↑ "Positional cloning of a novel Fanconi anemia gene, FANCD2". Molecular Cell 7 (2): 241–248. February 2001. doi:10.1016/S1097-2765(01)00172-1. PMID 11239453. 
  3. ↑ "The Fanconi Anemia/BRCA pathway: FANCD2 at the crossroad between repair and checkpoint responses to DNA damage.". Madame Curie Bioscience Database [Internet]. Landes Bioscience. 2013. https://www.ncbi.nlm.nih.gov/books/NBK6087/. 
  4. ↑ "The Fanconi anemia ubiquitin E3 ligase complex as an anti-cancer target". Molecular Cell 81 (11): 2278–2289. June 2021. doi:10.1016/j.molcel.2021.04.023. PMID 33984284. 
  5. ↑ "Susceptibility pathways in Fanconi's anemia and breast cancer". The New England Journal of Medicine 362 (20): 1909–1919. May 2010. doi:10.1056/NEJMra0809889. PMID 20484397. 
  6. ↑ "The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways". The Journal of Biological Chemistry 284 (38): 25560–25568. September 2009. doi:10.1074/jbc.M109.007690. PMID 19633289. 
  7. ↑ "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair 10 (5): 518–525. May 2011. doi:10.1016/j.dnarep.2011.02.007. PMID 21466974. 
  8. ↑ "Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability". Clinical Cancer Research 17 (3): 401–405. February 2011. doi:10.1158/1078-0432.CCR-10-1215. PMID 21088254. 
  9. ↑ "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood 100 (7): 2414–2420. October 2002. doi:10.1182/blood-2002-01-0278. PMID 12239151. 
  10. ↑ "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". Biochimica et Biophysica Acta 1846 (1): 263–275. August 2014. doi:10.1016/j.bbcan.2014.06.003. PMID 24998779. 
  11. ↑ "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. January 2013. doi:10.1128/MCB.00465-12. PMID 23149936. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway". Molecular Cell 7 (2): 249–262. February 2001. doi:10.1016/s1097-2765(01)00173-3. PMID 11239454. 
  13. ↑ "Monoubiquitination by the human Fanconi anemia core complex clamps FANCI:FANCD2 on DNA in filamentous arrays". eLife 9. March 2020. doi:10.7554/eLife.54128. PMID 32167469. 
  14. ↑ "Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability". Science 351 (6275): 846–849. February 2016. doi:10.1126/science.aad5634. PMID 26797144. Bibcode: 2016Sci...351..846L. 
  15. ↑ 15.0 15.1 15.2 "Mouse models of Fanconi anemia". Mutation Research 668 (1–2): 133–140. July 2009. doi:10.1016/j.mrfmmm.2009.03.015. PMID 19427003. Bibcode: 2009MRFMM.668..133P. 
  16. ↑ 16.0 16.1 "Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice". Genes & Development 17 (16): 2021–2035. August 2003. doi:10.1101/gad.1103403. PMID 12893777. 
  17. ↑ "Inhibition of USP28 overcomes Cisplatin-resistance of squamous tumors by suppression of the Fanconi anemia pathway". Cell Death and Differentiation 29 (3): 568–584. March 2022. doi:10.1038/s41418-021-00875-z. PMID 34611298. 
  18. ↑ "Methodology for the identification of small molecule inhibitors of the Fanconi Anaemia ubiquitin E3 ligase complex". Scientific Reports 10 (1): 7959. May 2020. doi:10.1038/s41598-020-64868-7. PMID 32409752. Bibcode: 2020NatSR..10.7959S. 
  19. ↑ "Cigarette smoke induces genetic instability in airway epithelial cells by suppressing FANCD2 expression". British Journal of Cancer 98 (10): 1653–1661. May 2008. doi:10.1038/sj.bjc.6604362. PMID 18475298. 
  20. ↑ "Uncoupling of transcription and translation of Fanconi anemia (FANC) complex proteins during spermatogenesis". Spermatogenesis 5 (1). 2015. doi:10.4161/21565562.2014.979061. PMID 26413409. 
  21. ↑ "FANCI protein binds to DNA and interacts with FANCD2 to recognize branched structures". The Journal of Biological Chemistry 284 (36): 24443–24452. September 2009. doi:10.1074/jbc.m109.016006. PMID 19561358. 
  22. ↑ "Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway". Science 333 (6040): 312–316. July 2011. doi:10.1126/science.1205805. PMID 21764741. Bibcode: 2011Sci...333..312J. 
  23. ↑ "Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways". Cell 109 (4): 459–472. May 2002. doi:10.1016/S0092-8674(02)00747-X. PMID 12086603. 
  24. ↑ 24.0 24.1 "Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport". Experimental Cell Research 289 (2): 211–221. October 2003. doi:10.1016/S0014-4827(03)00261-1. PMID 14499622. 
  25. ↑ 25.0 25.1 "BRCA1-independent ubiquitination of FANCD2". Molecular Cell 12 (1): 247–254. July 2003. doi:10.1016/S1097-2765(03)00281-8. PMID 12887909. 
  26. ↑ "Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin". Molecular and Cellular Biology 24 (13): 5850–5862. July 2004. doi:10.1128/MCB.24.13.5850-5862.2004. PMID 15199141. 
  27. ↑ 27.0 27.1 "Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways". Human Molecular Genetics 13 (12): 1241–1248. June 2004. doi:10.1093/hmg/ddh135. PMID 15115758. 
  28. ↑ 28.0 28.1 "Tip60 is required for DNA interstrand cross-link repair in the Fanconi anemia pathway". The Journal of Biological Chemistry 283 (15): 9844–9851. April 2008. doi:10.1074/jbc.M709076200. PMID 18263878. 
  29. ↑ "Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems". Blood 102 (1): 136–141. July 2003. doi:10.1182/blood-2002-11-3517. PMID 12649160. 
  30. ↑ "FANCE: the link between Fanconi anaemia complex assembly and activity". The EMBO Journal 21 (13): 3414–3423. July 2002. doi:10.1093/emboj/cdf355. PMID 12093742. 
  31. ↑ "Menin associates with FANCD2, a protein involved in repair of DNA damage". Cancer Research 63 (14): 4204–4210. July 2003. PMID 12874027. 

Further reading



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