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

Volumn 20, Issue 8, 2013, Pages 1089-1100

  Tilgner, K ^a,b   Neganova, I ^a,b   Moreno Gimeno, I ^c   Al Aama, J Y ^d   Burks, D ^c   Yung, S ^a,b   Singhapol, C ^a   Saretzki, G ^a   Evans, J ^a   Gorbunova, V ^e   Gennery, A ^a   Przyborski, S ^f   Stojkovic, M ^g   Armstrong, L ^a,b   Jeggo, P ^h   Lako, M ^a,b  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

^c CENTRO DE INVESTIGACIÓN PRÍNCIPE FELIPE   (Spain)

^d KING ABDULAZIZ UNIVERSITY   (Saudi Arabia)

^e UNIVERSITY OF ROCHESTER   (United States)

^f DURHAM UNIVERSITY   (United Kingdom)

^g UNIVERSITY OF KRAGUJEVAC   (Serbia)

^h UNIVERSITY OF SUSSEX   (United Kingdom)

Author keywords

Double strand break (DSB); Human pluripotent stem cells; Induced pluripotent stem cells (iPSC); Ionising radiation (IR); Ligase IV deficiency; Non homologous end joining (NHEJ)

Indexed keywords

DNA LIGASE IV; DSBA PROTEIN; LIGASE; PROTEIN P53; UNCLASSIFIED DRUG;

APOPTOSIS; ARTICLE; BLOOD CELL; BLOOD CELL COUNT; CELL DIFFERENTIATION; CELL EXPANSION; CELL SURVIVAL; CELL THERAPY; CHROMOSOME ABERRATION; CONTROLLED STUDY; DNA DAMAGE; DNA END JOINING REPAIR; DOUBLE STRANDED DNA BREAK; EMBRYOID BODY; ENZYME DEFICIENCY; EOSINOPHIL COUNT; FIBROBLAST; GENE MUTATION; GENE OVEREXPRESSION; GENETIC PREDISPOSITION; GENOME; GENOMIC INSTABILITY; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; HOMOLOGOUS RECOMBINATION; HUMAN; HUMAN CELL; LEUKEMIA; LIGASE IV DEFICIENCY; MICROCEPHALY; NUCLEAR REPROGRAMMING; PHENOTYPE; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROTEIN FUNCTION; SOMATIC CELL; STEM CELL;

APOPTOSIS; CELL LINE; CELL SURVIVAL; CELLS, CULTURED; DNA END-JOINING REPAIR; DNA LIGASES; GENOMIC INSTABILITY; HEMATOPOIETIC STEM CELLS; HUMANS; INDUCED PLURIPOTENT STEM CELLS; PHENOTYPE; TUMOR SUPPRESSOR PROTEIN P53; UP-REGULATION;

EID: 84880318361     PISSN: 13509047     EISSN: 14765403     Source Type: Journal    
DOI: 10.1038/cdd.2013.44     Document Type: Article

References (50)

1. Hartlerode AJ, Scully R. Mechanisms of double-strand break repair in somatic mammalian cells. Biochem J 2009; 423: 157-168.
2. Jeggo PA. DNA breakage and repair. Adv Genet 1998; 38: 185-218.
3. Holthausen JT, Wyman C, Kanaar R. Regulation of DNA strand exchange in homologous recombination. DNA Repair (Amst) 2010; 9: 1264-1272.
4. Lieber MR, Ma Y, Pannicke U, Schwarz K. Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol 2003; 4: 712-720.
5. Grawunder U, Grawunder U, Wilm M, Wu M, Kulesza P, Wilson TE et al. Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature 1997; 388: 492-495.
6. Ahnesorg P, Smith P, Jackson SP. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 2006; 124: 301-313.
7. Nussenzweig A, Nussenzweig MC. A backup DNA repair pathway moves to the forefront. Cell 2007; 131: 223-225.
8. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature 2009; 461: 1071-1078.
9. O'Driscoll M, Gennery AR, Seidel J, Concannon P, Jeggo PA. An overview of three new disorders associated with genetic instability: LIG4 syndrome, RS-SCID and ATR-Seckel syndrome. DNA Repair (Amst) 2004; 3: 1227-1235.
10. Frank KM, Sekiguchi JM, Seidl KJ, Swat W, Rathbun GA, Cheng HL et al. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 1998; 396: 173-177.
11. Frank KM, Sharpless NE, Gao Y, Sekiguchi JM, Ferguson DO, Zhu C et al. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell 2000; 5: 993-1002.
12. Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y, Seidl KJ et al. A critical role for DNA endjoining proteins in both lymphogenesis and neurogenesis. Cell 1998; 95: 891-902.
13. Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 2007; 447: 686-690.
14. Gatz SA, Ju L, Gruber R, Hoffmann E, Carr AM, Wang ZQ et al. Requirement for DNA ligase IV during embryonic neural development. J Neurosci 2011; 31: 10088-10100.
15. O'Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 2001; 8: 1175-1185.
16. Riballo E, Critchlow SE, Teo SH, Doherty AJ, Priestley A, Broughton B et al. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr Biol 1999; 9: 699-702.
17. Ben-Omran TI, Cerosaletti K, Concannon P, Weitzman S, Nezarati MM. A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet A 2005; 137A: 283-287.
18. Chistiakov DA. Ligase IV syndrome chapter 16: 175-183: Diseases of DNA repair, edited by S. I. Ahmad.
19. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 2007; 447: 725-729.
20. Zhang S, Yajima H, Huynh H, Zheng J, Callen E, Chen HT et al. Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair. J Cell Biol 2011; 193: 295-305.
21. Lucas D, Escudero B, Ligos JM, Segovia JC, Estrada JC, Terrados G et al. Altered hematopoiesis in mice lacking DNA polymerase mu is due to inefficient double-strand break repair. PLoS Genet 2009; 5: e1000389.
22. Nijnik A, Dawson S, Crockford TL, Woodbine L, Visetnoi S, Bennett S et al. Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome. J Clin Invest 2009; 119: 1696-1705.
23. Rucci F, Notarangelo LD, Fazeli A, Patrizi L, Hickernell T, Paganini T et al. Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome. Proc Natl Acad Sci USA 2010; 107: 3024-3029.
24. Mohrin M, Bourke E, Alexander D, Warr MR, Barry-Holson K, Le Beau MM et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 2010; 7: 174-185.
25. Saretzki G, Armstrong L, Leake A, Lako M, von Zglinicki T. Stress defense in murine embryonic stem cells is superior to that of various differentiated murine cells. Stem Cells 2004; 22: 962-971.
26. Saretzki G, Walter T, Atkinson S, Passos JF, Bareth B, Keith WN et al. Downregulation of multiple stress defence mechanisms during differentiation of human embryonic stem cells. Stem Cells 2008; 26: 455-464.
27. Bogomazova AN, Lagarkova MA, Tskhovrebova LV, Shutova MV, Kiselev SL. Error-prone nonhomologous end joining repair operates in human pluripotent stem cells during late G2. Aging 2011; 3: 584-596.
28. Fan J, Robert C, Jang YY, Liu H, Sharkis S, Baylin SB et al. Human induced pluripotent cells resemble embryonic stem cells demonstrating enhanced levels of DNA repair and efficacy of nonhomologous end-joining. Mutat Res 2011; 713: 8-17.
29. Roddam PL, Rollinson S, O'Driscoll M, Jeggo PA, Jack A, Morgan GJ. Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination. J Med Genet 2002; 39: 900-905.
30. Marión RM, Strati K, Li H, Murga M, Blanco R, Ortega S et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 2009; 460: 1149-1153.
31. Seluanov A, Mao Z, Gorbunova V. Analysis of DNA double-strand break (DSB) repair in mammalian cells. J Vis Exp 2002; 43, pii 2002.
32. Delacô te F, Han M, Stamato TD, Jasin M, Lopez BS. An xrcc4 defect or Wortmannin stimulates homologous recombination specifically induced by double-strand breaks in mammalian cells. Nuc Acids Res 2002; 30: 3454-3463.
33. Pierce AJ, Hu P, Han M, Ellis N, Jasin M. Ku DNA end-binding proteinmodulates homologous repair of double-strand breaks in mammalian cells. Genes Dev 2001; 15: 3237-3242.
34. Ohgushi M, Matsumura M, Eiraku M, Murakami K, Aramaki T, Nishiyama A et al. Molecular pathway and cell state responsible for dissociation-induced apoptosis in human pluripotent stem cells. Cell Stem Cell 2010; 7: 225-239.
35. Chen G, Hou Z, Gulbranson DR, Thomson JA. Actin-myosin contractility is responsible for the reduced viability of dissociated human embryonic stem cells. Cell Stem Cell 2010; 7: 240-248.
36. Kennedy M, D'Souza SL, Lynch-Kattman M, Schwantz S, Keller G. Development of the hemangioblast defines the onset of hematopoiesis in human ES cell differentiation cultures. Blood 2007; 109: 2679-2687.
37. Yung S, Ledran M, Moreno-Gimeno I, Conesa A, Montaner D, Dopazo J et al. Large-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells. Hum Mol Genet 2011; 20: 4932-4946.
38. Real PJ, Ligero G, Ayllon V, Ramos-Mejia V, Bueno C, Gutierrez-Aranda I et al. SCL/TAL1 regulates hematopoietic specification from human embryonic stem cells. Mol Ther 2012; 20: 1443-1453.
39. Bañuelos CA, Baná th JP, MacPhail SH, Zhao J, Eaves CA, O'Connor MD et al. Mouse but not human embryonic stem cells are deficient in rejoining of ionizing radiation-induced DNA double-strand breaks. DNA Repair (Amst) 2008; 7: 1471-1483.
40. Armstrong L, Tilgner K, Saretzki G, Atkinson SP, Stojkovic M, Moreno R et al. Human induced pluripotent stem cell lines show stress defense mechanisms and mitochondrial regulation similar to those of human embryonic stem cells. Stem Cells 2010; 28: 661-673.
41. Mayshar Y, Ben-David U, Lavon N, Biancotti JC, Yakir B, Clark AT et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 2010; 7: 521-531.
42. Elliott AM, Elliott KA, Kammesheidt A. High resolution array-CGH characterization of human stem cells using a stem cell focused microarray. Mol Biotech 2010; 46: 234-242.
43. Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R et al. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 2011; 8: 106-118.
44. International Stem Cell InitiativeAmps K, Andrews PW, Anyfantis G, Armstrong L, Avery S, Baharvand H et al. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat Biotech 2011; 29: 1132-1144.
45. Martins-Taylor K, Nisler BS, Taapken SM, Compton T, Crandall L, Montgomery KD et al. Recurrent copy number variations in human induced pluripotent stem cells. Nat Biotech 2011; 29: 488-491.
46. Yung SK, Tilgner K, Ledran MH, Habibollah S, Neganova I, Singhapol C et al. Human pluripotent stem cell models of Fanconi Anaemia deficiency reveal an important role for Fanconi Anaemia proteins in cellular reprogramming and survival of haematopoietic progenitors. Stem Cells 2013; 31: 1022-1029.
47. Müller LU, Milsom MD, Harris CE, Vyas R, Brumme KM, Parmar K et al. Overcoming reprogramming resistance of Fanconi anemia cells. Blood 2012; 119: 5449-5457.
48. Stojkovic M, Lako M, Stojkovic P, Stewart R, Przyborski S, Armstrong L et al. Derivation of human embryonic stem cells from day-8 blastocysts recovered after three-step in vitro culture. Stem Cells 2004; 22: 790-797.
49. Neganova I, Zhang X, Atkinson S, Lako M. Expression and functional analysis of G1 to S regulatory components reveals an important role for CDK2 in cell cycle regulation in human embryonic stem cells. Oncogene 2008; 28: 20-30.
50. Mellough CB, Sernagor E, Moreno-Gimeno I, Steel DH, Lako M. Efficient stage-specific differentiation of human pluripotent stem cells toward retinal photoreceptor cells. Stem Cells 2012; 30: 673-686.