| Structural highlights
Function
XRCC4_HUMAN Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. Binds to DNA and to DNA ligase IV (LIG4). The LIG4-XRCC4 complex is responsible for the NHEJ ligation step, and XRCC4 enhances the joining activity of LIG4. Binding of the LIG4-XRCC4 complex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends.[1] [2] [3] [4]
Publication Abstract from PubMed
Chromosome translocation is a major cause of the onset and progression of diverse types of cancers. However, the mechanisms underlying this process remain poorly understood. Here, we identified a non-homologous end-joining protein, IFFO1, which structurally forms a heterotetramer with XRCC4. IFFO1 is recruited to the sites of DNA damage by XRCC4 and promotes the repair of DNA double-strand breaks in a parallel pathway with XLF. Interestingly, IFFO1 interacts with lamin A/C, forming an interior nucleoskeleton. Inactivating IFFO1 or its interaction with XRCC4 or lamin A/C leads to increases in both the mobility of broken ends and the frequency of chromosome translocation. Importantly, the destruction of this nucleoskeleton accounts for the elevated frequency of chromosome translocation in many types of cancer cells. Our results reveal that the lamin A/C-IFFO1-constituted nucleoskeleton prevents chromosome translocation by immobilizing broken DNA ends during tumorigenesis.
The nucleoskeleton protein IFFO1 immobilizes broken DNA and suppresses chromosome translocation during tumorigenesis.,Li W, Bai X, Li J, Zhao Y, Liu J, Zhao H, Liu L, Ding M, Wang Q, Shi FY, Hou M, Ji J, Gao G, Guo R, Sun Y, Liu Y, Xu D Nat Cell Biol. 2019 Oct;21(10):1273-1285. doi: 10.1038/s41556-019-0388-0. Epub, 2019 Sep 23. PMID:31548606[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Li Z, Otevrel T, Gao Y, Cheng HL, Seed B, Stamato TD, Taccioli GE, Alt FW. The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination. Cell. 1995 Dec 29;83(7):1079-89. PMID:8548796
- ↑ Chen L, Trujillo K, Sung P, Tomkinson AE. Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase. J Biol Chem. 2000 Aug 25;275(34):26196-205. PMID:10854421 doi:10.1074/jbc.M000491200
- ↑ Nick McElhinny SA, Snowden CM, McCarville J, Ramsden DA. Ku recruits the XRCC4-ligase IV complex to DNA ends. Mol Cell Biol. 2000 May;20(9):2996-3003. PMID:10757784
- ↑ Foster RE, Nnakwe C, Woo L, Frank KM. Monoubiquitination of the nonhomologous end joining protein XRCC4. Biochem Biophys Res Commun. 2006 Mar 3;341(1):175-83. Epub 2006 Jan 6. PMID:16412978 doi:S0006-291X(05)02903-7
- ↑ Li W, Bai X, Li J, Zhao Y, Liu J, Zhao H, Liu L, Ding M, Wang Q, Shi FY, Hou M, Ji J, Gao G, Guo R, Sun Y, Liu Y, Xu D. The nucleoskeleton protein IFFO1 immobilizes broken DNA and suppresses chromosome translocation during tumorigenesis. Nat Cell Biol. 2019 Oct;21(10):1273-1285. doi: 10.1038/s41556-019-0388-0. Epub, 2019 Sep 23. PMID:31548606 doi:http://dx.doi.org/10.1038/s41556-019-0388-0
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