LIG4
| |
| PDB 1ik9 | |
LIG4
| |
| Identificadores | |
| Símbolo | LIG4 |
| Símbolos alt. | LIG4S, DNA ligase 4 |
| Entrez | 3981 |
| PDB | PDB [http://www.rcsb.org/pdb/explore/explore.do?structureId=1IK9 1IK9, PDB 2E2W, PDB 3II6, PDB 3VNN, PDB 3W1B, PDB 3W1G, PDB 3W5O, PDB 4HTO, PDB 4HTP PDB 1IK9, PDB 2E2W, PDB 3II6, PDB 3VNN, PDB 3W1B, PDB 3W1G, PDB 3W5O, PDB 4HTO, PDB 4HTP] |
| RefSeq | NP_001091738.1 |
| UniProt | P49917 |
| Outros datos | |
| Locus | Cr. 13 :(108.21 – 108.22 Mb) |
O LIG4 é un xene humano situado no cromosoma 13 que codifica a proteína ADN ligase IV (tamén chamada LIG4 ou Lig4).[1]
Función
editarA proteína codificada por este xene é unha ADN ligase dependente de ATP que une as roturas de dobre febra durante o proceso de reparación por unión de extremos non homólogos. Tamén é esencial para a recombinación V(D)J. A Lig4 forma un complexo con XRCC4, e despois interacciona coa proteína quinase dependente do ADN (DNA-PK) e XLF/Cernunnos, que son tamén necesarias para a NHEJ. Resolveuse a estrutura cristalina do complexo Lig4/XRCC4.[2] Os defectos no xene LIG4 son a causa da síndrome LIG4. O homólogo en lévedos de Lig4 é Dnl4.
Síndrome LIG4
editarEn humanos, a deficiencia de ADN ligase 4 ten como resultado unha condicións clínica chamada síndrome LIG4. Esta síndrome está caracterizada por sensibilidade á radiación celular, retardo do crecemento e do desenvolvemento, microcefalia, dismorfismos faciais, incremento da disposición a padecer leucemia, graos variables de inmunodeficiencia e redución do número de células sanguíneas.[3][4]
Envellecemento por causa das células nai hematopoéticas
editarA acumulación de danos no ADN orixina o esgotamento de células nai e considérase un importante aspecto no envellecemento.[5][6] A deficiencia de Lig4 en células nai pluripotentes altera a unión de extremos non homólogos (NHEJ) e causa a acumulación de roturas de dobre febra no ADN e potencia a apoptose.[4] A deficiencia de Lig4 en ratos causa unha perda progresiva de células nai hematopoéticas e de celularidade na medula ósea durante o envellecemento.[7] A sensibilidade das células nai hematopoéticas á deficiencia de Lig4 suxire que a NHEJ mediada por Lig4 é un determinante clave da capacidade das células nai de manterse co tempo fronte aos estreses fisiolóxicos.[4][7]
Interaccións
editarA Lig4 presenta interaccións con XRCC4 por medio do seu dominio BRCT.[2][8] Esta interacción estabiliza a proteína Lig4 nas células; as células que son deficientes en XRCC4, como as células XR-1, teñen niveis reducidos de Lig4.[9]
Mecanismo
editarA proteína Lig4 é unha ADN ligase dependente do ATP. A Lig4 usa o ATP para adenilarse a si mesma e despois transfire o grupo AMP ao fosfato 5' dun extremo do ADN. Prodúcese un ataque nucleofílico polo grupo hidroxilo 3' dun segundo extremo do ADN e libera o AMP e orixina o produto de ligazón. A adenilación de Lig4 é estimulada por XRCC4 e o XLF.[10]
Notas
editar- ↑ "Entrez Gene: LIG4 ligase IV, DNA, ATP-dependent".
- ↑ 2,0 2,1 Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL, Pellegrini L (Dec 2001). "Crystal structure of an Xrcc4-DNA ligase IV complex". Nature Structural Biology 8 (12): 1015–9. PMID 11702069. doi:10.1038/nsb725.
- ↑ Rucci F, Notarangelo LD, Fazeli A, Patrizi L, Hickernell T, Paganini T, Coakley KM, Detre C, Keszei M, Walter JE, Feldman L, Cheng HL, Poliani PL, Wang JH, Balter BB, Recher M, Andersson EM, Zha S, Giliani S, Terhorst C, Alt FW, Yan CT (Feb 2010). "Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome". Proceedings of the National Academy of Sciences of the United States of America 107 (7): 3024–9. PMC 2840307. PMID 20133615. doi:10.1073/pnas.0914865107.
- ↑ 4,0 4,1 4,2 Tilgner K, Neganova I, Moreno-Gimeno I, Al-Aama JY, Burks D, Yung S, Singhapol C, Saretzki G, Evans J, Gorbunova V, Gennery A, Przyborski S, Stojkovic M, Armstrong L, Jeggo P, Lako M (Aug 2013). "A human iPSC model of Ligase IV deficiency reveals an important role for NHEJ-mediated-DSB repair in the survival and genomic stability of induced pluripotent stem cells and emerging haematopoietic progenitors". Cell Death and Differentiation 20 (8): 1089–100. PMC 3705601. PMID 23722522. doi:10.1038/cdd.2013.44.
- ↑ Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL (Jun 2007). "Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age". Nature 447 (7145): 725–9. PMID 17554309. doi:10.1038/nature05862.
- ↑ Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 Arquivado 25 de outubro de 2014 en Wayback Machine. ISBN 1604565810 ISBN 978-1604565812
- ↑ 7,0 7,1 Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, Rodrigues NP, Crockford TL, Cabuy E, Vindigni A, Enver T, Bell JI, Slijepcevic P, Goodnow CC, Jeggo PA, Cornall RJ (Jun 2007). "DNA repair is limiting for haematopoietic stem cells during ageing". Nature 447 (7145): 686–90. PMID 17554302. doi:10.1038/nature05875.
- ↑ Deshpande RA, Wilson TE (Oct 2007). "Modes of interaction among yeast Nej1, Lif1 and Dnl4 proteins and comparison to human XLF, XRCC4 and Lig4". DNA Repair 6 (10): 1507–16. PMC 2064958. PMID 17567543. doi:10.1016/j.dnarep.2007.04.014.
- ↑ Bryans M, Valenzano MC, Stamato TD (Jan 1999). "Absence of DNA ligase IV protein in XR-1 cells: evidence for stabilization by XRCC4". Mutation Research 433 (1): 53–8. PMID 10047779. doi:10.1016/s0921-8777(98)00063-9.
- ↑ Mahaney BL, Hammel M, Meek K, Tainer JA, Lees-Miller SP (Feb 2013). "XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair". Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire 91 (1): 31–41. PMID 23442139. doi:10.1139/bcb-2012-0058.
Véxase tamén
editarBibliografía
editar- Wei YF, Robins P, Carter K, Caldecott K, Pappin DJ, Yu GL, Wang RP, Shell BK, Nash RA, Schär P (Jun 1995). "Molecular cloning and expression of human cDNAs encoding a novel DNA ligase IV and DNA ligase III, an enzyme active in DNA repair and recombination". Molecular and Cellular Biology 15 (6): 3206–16. PMC 230553. PMID 7760816. doi:10.1128/mcb.15.6.3206.
- Robins P, Lindahl T (Sep 1996). "DNA ligase IV from HeLa cell nuclei". The Journal of Biological Chemistry 271 (39): 24257–61. PMID 8798671. doi:10.1074/jbc.271.39.24257.
- Grawunder U, Wilm M, Wu X, Kulesza P, Wilson TE, Mann M, Lieber MR (Jul 1997). "Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells". Nature 388 (6641): 492–5. PMID 9242410. doi:10.1038/41358.
- Critchlow SE, Bowater RP, Jackson SP (Aug 1997). "Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV". Current Biology 7 (8): 588–98. PMID 9259561. doi:10.1016/S0960-9822(06)00258-2.
- Grawunder U, Zimmer D, Lieber MR (Jul 1998). "DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains". Current Biology 8 (15): 873–6. PMID 9705934. doi:10.1016/S0960-9822(07)00349-1.
- Grawunder U, Zimmer D, Fugmann S, Schwarz K, Lieber MR (Oct 1998). "DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes". Molecular Cell 2 (4): 477–84. PMID 9809069. doi:10.1016/S1097-2765(00)80147-1.
- Riballo E, Critchlow SE, Teo SH, Doherty AJ, Priestley A, Broughton B, Kysela B, Beamish H, Plowman N, Arlett CF, Lehmann AR, Jackson SP, Jeggo PA (Jul 1999). "Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient". Current Biology 9 (13): 699–702. PMID 10395545. doi:10.1016/S0960-9822(99)80311-X.
- Kim ST, Lim DS, Canman CE, Kastan MB (Dec 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". The Journal of Biological Chemistry 274 (53): 37538–43. PMID 10608806. doi:10.1074/jbc.274.53.37538.
- Nick McElhinny SA, Snowden CM, McCarville J, Ramsden DA (May 2000). "Ku recruits the XRCC4-ligase IV complex to DNA ends". Molecular and Cellular Biology 20 (9): 2996–3003. PMC 85565. PMID 10757784. doi:10.1128/MCB.20.9.2996-3003.2000.
- Chen L, Trujillo K, Sung P, Tomkinson AE (Aug 2000). "Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase". The Journal of Biological Chemistry 275 (34): 26196–205. PMID 10854421. doi:10.1074/jbc.M000491200.
- Lee KJ, Huang J, Takeda Y, Dynan WS (Nov 2000). "DNA ligase IV and XRCC4 form a stable mixed tetramer that functions synergistically with other repair factors in a cell-free end-joining system". The Journal of Biological Chemistry 275 (44): 34787–96. PMID 10945980. doi:10.1074/jbc.M004011200.
- Riballo E, Doherty AJ, Dai Y, Stiff T, Oettinger MA, Jeggo PA, Kysela B (Aug 2001). "Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity". The Journal of Biological Chemistry 276 (33): 31124–32. PMID 11349135. doi:10.1074/jbc.M103866200.
- Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL, Pellegrini L (Dec 2001). "Crystal structure of an Xrcc4-DNA ligase IV complex". Nature Structural Biology 8 (12): 1015–9. PMID 11702069. doi:10.1038/nsb725.
- O'Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer SE, Seidel J, Gatti RA, Varon R, Oettinger MA, Neitzel H, Jeggo PA, Concannon P (Dec 2001). "DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency". Molecular Cell 8 (6): 1175–85. PMID 11779494. doi:10.1016/S1097-2765(01)00408-7.
- Kuschel B, Auranen A, McBride S, Novik KL, Antoniou A, Lipscombe JM, Day NE, Easton DF, Ponder BA, Pharoah PD, Dunning A (Jun 2002). "Variants in DNA double-strand break repair genes and breast cancer susceptibility". Human Molecular Genetics 11 (12): 1399–407. PMID 12023982. doi:10.1093/hmg/11.12.1399.
- Mahajan KN, Nick McElhinny SA, Mitchell BS, Ramsden DA (Jul 2002). "Association of DNA polymerase mu (pol mu) with Ku and ligase IV: role for pol mu in end-joining double-strand break repair". Molecular and Cellular Biology 22 (14): 5194–202. PMC 139779. PMID 12077346. doi:10.1128/MCB.22.14.5194-5202.2002.
- Roth DB (Jul 2002). "Amplifying mechanisms of lymphomagenesis". Molecular Cell 10 (1): 1–2. PMID 12150897. doi:10.1016/S1097-2765(02)00573-7.
- Smogorzewska A, Karlseder J, Holtgreve-Grez H, Jauch A, de Lange T (Oct 2002). "DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2". Current Biology 12 (19): 1635–44. PMID 12361565. doi:10.1016/S0960-9822(02)01179-X.
- Roddam PL, Rollinson S, O'Driscoll M, Jeggo PA, Jack A, Morgan GJ (Dec 2002). "Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination". Journal of Medical Genetics 39 (12): 900–5. PMC 1757220. PMID 12471202. doi:10.1136/jmg.39.12.900.