3sr2

Structural highlights

Disease

[NHEJ1_HUMAN] Defects in NHEJ1 are the cause of severe combined immunodeficiency due to NHEJ1 deficiency (NHEJ1-SCID) [MIM:611291]; also known as autosomal recessive T-cell-negative, B-cell-negative, NK cell-positive, severe combined immunodeficiency with microcephaly, growth retardation and sensitivity to ionizing radiation or NHEJ1 syndrome. SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. NHEJ1-SCID is characterized by a profound T- and B-lymphocytopenia associated with increased cellular sensitivity to ionizing radiation, microcephaly and growth retardation. Some patients may manifest SCID with sensitivity to ionizing radiation without microcephaly and mild growth retardation, probably due to hypomorphic NHEJ1 mutations.^{[1] [2] [3] [4]} Note=A chromosomal aberration involving NHEJ1 is found in a patient with polymicrogyria. Translocation t(2;7)(q35;p22).^[5]

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.^{[6] [7] [8] [9]} [NHEJ1_HUMAN] DNA repair protein involved in DNA nonhomologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. May serve as a bridge between XRCC4 and the other NHEJ factors located at DNA ends, or may participate in reconfiguration of the end bound NHEJ factors to allow XRCC4 access to the DNA termini. It may act in concert with XRCC6/XRCC5 (Ku) to stimulate XRCC4-mediated joining of blunt ends and several types of mismatched ends that are noncomplementary or partially complementary.^{[10] [11] [12]}

References

1. ↑ Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche MC, Sanal O, Plebani A, Stephan JL, Hufnagel M, le Deist F, Fischer A, Durandy A, de Villartay JP, Revy P. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell. 2006 Jan 27;124(2):287-99. PMID:16439204 doi:S0092-8674(06)00002-X
2. ↑ Ahnesorg P, Smith P, Jackson SP. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell. 2006 Jan 27;124(2):301-13. PMID:16439205 doi:S0092-8674(06)00003-1
3. ↑ Lu H, Pannicke U, Schwarz K, Lieber MR. Length-dependent binding of human XLF to DNA and stimulation of XRCC4.DNA ligase IV activity. J Biol Chem. 2007 Apr 13;282(15):11155-62. Epub 2007 Feb 21. PMID:17317666 doi:M609904200
4. ↑ Dai Y, Kysela B, Hanakahi LA, Manolis K, Riballo E, Stumm M, Harville TO, West SC, Oettinger MA, Jeggo PA. Nonhomologous end joining and V(D)J recombination require an additional factor. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2462-7. Epub 2003 Feb 25. PMID:12604777 doi:10.1073/pnas.0437964100
5. ↑ Dai Y, Kysela B, Hanakahi LA, Manolis K, Riballo E, Stumm M, Harville TO, West SC, Oettinger MA, Jeggo PA. Nonhomologous end joining and V(D)J recombination require an additional factor. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2462-7. Epub 2003 Feb 25. PMID:12604777 doi:10.1073/pnas.0437964100
6. ↑ 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
7. ↑ 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
8. ↑ 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
9. ↑ 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
10. ↑ Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche MC, Sanal O, Plebani A, Stephan JL, Hufnagel M, le Deist F, Fischer A, Durandy A, de Villartay JP, Revy P. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell. 2006 Jan 27;124(2):287-99. PMID:16439204 doi:S0092-8674(06)00002-X
11. ↑ Ahnesorg P, Smith P, Jackson SP. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell. 2006 Jan 27;124(2):301-13. PMID:16439205 doi:S0092-8674(06)00003-1
12. ↑ Tsai CJ, Kim SA, Chu G. Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends. Proc Natl Acad Sci U S A. 2007 May 8;104(19):7851-6. Epub 2007 Apr 30. PMID:17470781 doi:0702620104
13. ↑ Hammel M, Rey M, Yu Y, Mani RS, Classen S, Liu M, Pique ME, Fang S, Mahaney B, Weinfeld M, Schriemer DC, Lees-Miller SP, Tainer JA. XRCC4 interactions with XRCC4-like factor (XLF) create an extended grooved scaffold for DNA ligation and double-strand break repair. J Biol Chem. 2011 Jul 20. PMID:21775435 doi:10.1074/jbc.M111.272641