FANCD2
Ensembl |
| ||||||||
|---|---|---|---|---|---|---|---|---|---|
| UniProt | |||||||||
| RefSeq (mRNA) |
| ||||||||
| RefSeq (protein) |
| ||||||||
| Location (UCSC) | Chr 3: 10.03 – 10.1 Mb | n/a | |||||||
| PubMed search | [2] | [3] | |||||||
| View/Edit Human | View/Edit Mouse |
Fanconi anemia group D2 protein is a
Function
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.[14]
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.[15]
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.[16]
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.[17] In synaptonemal complexes of meiotic chromosomes, activated FANCD2 protein co-localizes with BRCA1 (breast cancer susceptibility protein).[13] FANCD2 mutant mice exhibit chromosome mis-pairing during the pachytene stage of meiosis and germ cell loss.[18] 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.[13]
Clinical significance
Tobacco smoke suppresses the expression of FANCD2, which codes for a DNA damage "caretaker" or repair mechanism.[19]
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.[16][18] Humans with a FANCD2 deficiency have increased acute myeloid leukemia, and squamous cell carcinomas (head and neck squamous cell carcinomas and anogenital carcinomas).[16] Lung squamous tumors express high levels of FANCD2 and members of Fanconia anemia pathway.[20]
FANCD2 monoubiquitination is also a potential therapeutic target in the treatment of cancer.[21]
Interactions
FANCD2 has been shown to
- FANCI[22][23]
- BARD1,[26]
- BRCA1.[25][26]
- BRCA2,[27][28][29]
- FANCE,[28][30][31]
- HTATIP,[29]and
- MEN1.[32]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000144554 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 451042.
- PMID 11239453.
- PMID 20484397.
- PMID 19633289.
- PMID 21466974.
- PMID 21088254.
- PMID 12239151.
- PMID 24998779.
- PMID 23149936.
- ^ PMID 11239454.
- PMID 32167469.
- PMID 26797144.
- ^ PMID 19427003.
- PMID 26413409.
- ^ PMID 12893777.
- PMID 18475298.
- bioRxiv 10.1101/2020.09.10.291278.
- PMID 32409752.
- PMID 19561358.
- PMID 21764741.
- S2CID 16580666.
- ^ PMID 14499622.
- ^ PMID 12887909.
- PMID 15199141.
- ^ PMID 15115758.
- ^ PMID 18263878.
- PMID 12649160.
- PMID 12093742.
- PMID 12874027.
External links
| Other forms of repair |
| |
|---|---|---|
| Other/ungrouped proteins | ||
| Regulation | ||
| Other/ungrouped |
| |
Further reading
- Hejna JA, Timmers CD, Reifsteck C, Bruun DA, Lucas LW, Jakobs PM, et al. (May 2000). "Localization of the Fanconi anemia complementation group D gene to a 200-kb region on chromosome 3p25.3". American Journal of Human Genetics. 66 (5): 1540–51. PMID 10762542.
- Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, et al. (February 2001). "Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway". Molecular Cell. 7 (2): 249–62. PMID 11239454.
- Futaki M, Liu JM (December 2001). "Chromosomal breakage syndromes and the BRCA1 genome surveillance complex". Trends in Molecular Medicine. 7 (12): 560–5. PMID 11733219.
- Wilson JB, Johnson MA, Stuckert AP, Trueman KL, May S, Bryant PE, et al. (December 2001). "The Chinese hamster FANCG/XRCC9 mutant NM3 fails to express the monoubiquitinated form of the FANCD2 protein, is hypersensitive to a range of DNA damaging agents and exhibits a normal level of spontaneous sister chromatid exchange". Carcinogenesis. 22 (12): 1939–46. PMID 11751423.
- Grompe M (June 2002). "FANCD2: a branch-point in DNA damage response?". Nature Medicine. 8 (6): 555–6. S2CID 27843912.
- Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST, et al. (May 2002). "Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways". Cell. 109 (4): 459–72. S2CID 16580666.
- Pace P, Johnson M, Tan WM, Mosedale G, Sng C, Hoatlin M, et al. (July 2002). "FANCE: the link between Fanconi anaemia complex assembly and activity". The EMBO Journal. 21 (13): 3414–23. PMID 12093742.
- Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD (October 2002). "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood. 100 (7): 2414–20. PMID 12239151.
- Tamary H, Bar-Yam R, Zemach M, Dgany O, Shalmon L, Yaniv I (October 2002). "The molecular biology of Fanconi anemia". The Israel Medical Association Journal. 4 (10): 819–23. PMID 12389351.
- Nakanishi K, Taniguchi T, Ranganathan V, New HV, Moreau LA, Stotsky M, et al. (December 2002). "Interaction of FANCD2 and NBS1 in the DNA damage response". Nature Cell Biology. 4 (12): 913–20. S2CID 20807784.
- Goldberg M, Stucki M, Falck J, D'Amours D, Rahman D, Pappin D, et al. (February 2003). "MDC1 is required for the intra-S-phase DNA damage checkpoint". Nature. 421 (6926): 952–6. S2CID 4301037.
- Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ (February 2003). "MDC1 is a mediator of the mammalian DNA damage checkpoint". Nature. 421 (6926): 961–6. S2CID 4410773.
- Gordon SM, Buchwald M (July 2003). "Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems". Blood. 102 (1): 136–41. PMID 12649160.
- Jin S, Mao H, Schnepp RW, Sykes SM, Silva AC, D'Andrea AD, Hua X (July 2003). "Menin associates with FANCD2, a protein involved in repair of DNA damage". Cancer Research. 63 (14): 4204–10. PMID 12874027.
- Vandenberg CJ, Gergely F, Ong CY, Pace P, Mallery DL, Hiom K, Patel KJ (July 2003). "BRCA1-independent ubiquitination of FANCD2". Molecular Cell. 12 (1): 247–54. PMID 12887909.
- Meetei AR, de Winter JP, Medhurst AL, Wallisch M, Waisfisz Q, van de Vrugt HJ, et al. (October 2003). "A novel ubiquitin ligase is deficient in Fanconi anemia". Nature Genetics. 35 (2): 165–70. S2CID 10149290.
- Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H, et al. (October 2003). "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): 211–21. PMID 14499622.
- Wang X, Kennedy RD, Ray K, Stuckert P, Ellenberger T, D'Andrea AD (April 2007). "Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA pathway". Molecular and Cellular Biology. 27 (8): 3098–108. PMID 17296736.