| Structural highlights
Disease
[FACD2_HUMAN] Fanconi anemia. The disease is caused by mutations affecting the gene represented in this entry.
Function
[UBC_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[1] [2] [FACD2_HUMAN] Required for maintenance of chromosomal stability. Promotes accurate and efficient pairing of homologs during meiosis. Involved in the repair of DNA double-strand breaks, both by homologous recombination and single-strand annealing. May participate in S phase and G2 phase checkpoint activation upon DNA damage. Plays a role in preventing breakage and loss of missegregating chromatin at the end of cell division, particularly after replication stress. Required for the targeting, or stabilization, of BLM to non-centromeric abnormal structures induced by replicative stress. Promotes BRCA2/FANCD1 loading onto damaged chromatin. May also be involved in B-cell immunoglobulin isotype switching.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
Publication Abstract from PubMed
The ID complex, involving the proteins FANCI and FANCD2, is required for the repair of DNA interstrand crosslinks (ICL) and related lesions(1). These proteins are mutated in Fanconi anaemia, a disease in which patients are predisposed to cancer. The Fanconi anaemia pathway of ICL repair is activated when a replication fork stalls at an ICL(2); this triggers monoubiquitination of the ID complex, in which one ubiquitin molecule is conjugated to each of FANCI and FANCD2. Monoubiquitination of ID is essential for ICL repair by excision, translesion synthesis and homologous recombination; however, its function remains unknown(1,3). Here we report a cryo-electron microscopy structure of the monoubiquitinated human ID complex bound to DNA, and reveal that it forms a closed ring that encircles the DNA. By comparison with the structure of the non-ubiquitinated ID complex bound to ICL DNA-which we also report here-we show that monoubiquitination triggers a complete rearrangement of the open, trough-like ID structure through the ubiquitin of one protomer binding to the other protomer in a reciprocal fashion. These structures-together with biochemical data-indicate that the monoubiquitinated ID complex loses its preference for ICL and related branched DNA structures, and becomes a sliding DNA clamp that can coordinate the subsequent repair reactions. Our findings also reveal how monoubiquitination in general can induce an alternative protein structure with a new function.
DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex.,Wang R, Wang S, Dhar A, Peralta C, Pavletich NP Nature. 2020 Apr;580(7802):278-282. doi: 10.1038/s41586-020-2110-6. Epub 2020 Mar, 11. PMID:32269332[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006 Mar 17;21(6):737-48. PMID:16543144 doi:S1097-2765(06)00120-1
- ↑ Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53. doi: 10.1042/BST0370937. PMID:19754430 doi:10.1042/BST0370937
- ↑ 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. Positional cloning of a novel Fanconi anemia gene, FANCD2. Mol Cell. 2001 Feb;7(2):241-8. PMID:11239453
- ↑ Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D'Andrea AD. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell. 2001 Feb;7(2):249-62. PMID:11239454
- ↑ Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST, Lane WS, Kastan MB, D'Andrea AD. Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell. 2002 May 17;109(4):459-72. PMID:12086603
- ↑ Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD. S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood. 2002 Oct 1;100(7):2414-20. doi: 10.1182/blood-2002-01-0278. PMID:12239151 doi:http://dx.doi.org/10.1182/blood-2002-01-0278
- ↑ Holzel M, van Diest PJ, Bier P, Wallisch M, Hoatlin ME, Joenje H, de Winter JP. FANCD2 protein is expressed in proliferating cells of human tissues that are cancer-prone in Fanconi anaemia. J Pathol. 2003 Oct;201(2):198-203. doi: 10.1002/path.1450. PMID:14517836 doi:http://dx.doi.org/10.1002/path.1450
- ↑ 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. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways. Hum Mol Genet. 2004 Jun 15;13(12):1241-8. Epub 2004 Apr 28. PMID:15115758 doi:10.1093/hmg/ddh135
- ↑ Andreassen PR, D'Andrea AD, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 2004 Aug 15;18(16):1958-63. PMID:15314022 doi:http://dx.doi.org/10.1101/gad.1196104
- ↑ Freie BW, Ciccone SL, Li X, Plett PA, Orschell CM, Srour EF, Hanenberg H, Schindler D, Lee SH, Clapp DW. A role for the Fanconi anemia C protein in maintaining the DNA damage-induced G2 checkpoint. J Biol Chem. 2004 Dec 3;279(49):50986-93. doi: 10.1074/jbc.M407160200. Epub 2004 , Sep 17. PMID:15377654 doi:http://dx.doi.org/10.1074/jbc.M407160200
- ↑ Montes de Oca R, Andreassen PR, Margossian SP, Gregory RC, Taniguchi T, Wang X, Houghtaling S, Grompe M, D'Andrea AD. Regulated interaction of the Fanconi anemia protein, FANCD2, with chromatin. Blood. 2005 Feb 1;105(3):1003-9. doi: 10.1182/blood-2003-11-3997. Epub 2004 Sep, 28. PMID:15454491 doi:http://dx.doi.org/10.1182/blood-2003-11-3997
- ↑ Nakanishi K, Yang YG, Pierce AJ, Taniguchi T, Digweed M, D'Andrea AD, Wang ZQ, Jasin M. Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair. Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1110-5. Epub 2005 Jan 13. PMID:15650050 doi:http://dx.doi.org/0407796102
- ↑ Howlett NG, Taniguchi T, Durkin SG, D'Andrea AD, Glover TW. The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability. Hum Mol Genet. 2005 Mar 1;14(5):693-701. doi: 10.1093/hmg/ddi065. Epub 2005 Jan, 20. PMID:15661754 doi:http://dx.doi.org/10.1093/hmg/ddi065
- ↑ Ohashi A, Zdzienicka MZ, Chen J, Couch FJ. Fanconi anemia complementation group D2 (FANCD2) functions independently of BRCA2- and RAD51-associated homologous recombination in response to DNA damage. J Biol Chem. 2005 Apr 15;280(15):14877-83. Epub 2005 Jan 25. PMID:15671039 doi:M414669200
- ↑ Naim V, Rosselli F. The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. Nat Cell Biol. 2009 Jun;11(6):761-8. doi: 10.1038/ncb1883. Epub 2009 May 24. PMID:19465921 doi:http://dx.doi.org/10.1038/ncb1883
- ↑ Wang R, Wang S, Dhar A, Peralta C, Pavletich NP. DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex. Nature. 2020 Apr;580(7802):278-282. doi: 10.1038/s41586-020-2110-6. Epub 2020 Mar, 11. PMID:32269332 doi:http://dx.doi.org/10.1038/s41586-020-2110-6
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