Skip to main content

Homing endonucleases: from basics to therapeutic applications

Abstract

Homing endonucleases (HE) are double-stranded DNAses that target large recognition sites (12–40 bp). HE-encoding sequences are usually embedded in either introns or inteins. Their recognition sites are extremely rare, with none or only a few of these sites present in a mammalian-sized genome. However, these enzymes, unlike standard restriction endonucleases, tolerate some sequence degeneracy within their recognition sequence. Several members of this enzyme family have been used as templates to engineer tools to cleave DNA sequences that differ from their original wild-type targets. These custom HEs can be used to stimulate double-strand break homologous recombination in cells, to induce the repair of defective genes with very low toxicity levels. The use of tailored HEs opens up new possibilities for gene therapy in patients with monogenic diseases that can be treated ex vivo. This review provides an overview of recent advances in this field.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Dujon B (2005) Homing nucleases and the yeast mitochondrial omega locus: a historical perspective, vol 16. Springer, Berlin

    Google Scholar 

  2. Liu Q, Belle A, Shub DA, Belfort M, Edgell DR (2003) SegG endonuclease promotes marker exclusion and mediates co-conversion from a distant cleavage site. J Mol Biol 334:13–23

    PubMed  CAS  Google Scholar 

  3. Edgell DR (2005) Free-standing homing endonucleases of T-even phage: freeloaders or functionaries?, vol 16. Springer, Berlin

    Google Scholar 

  4. Edgell DR (2002) Selfish DNA: new abode for homing endonucleases. Curr Biol 12:R276–R278. doi:S0960982202007996[pii]

    PubMed  CAS  Google Scholar 

  5. Kobayashi I (2001) Behavior of restriction-modification systems as selfish mobile elements and their impact on genome evolution. Nucleic Acids Res 29:3742–3756

    PubMed  CAS  Google Scholar 

  6. Roberts RJ, Belfort M, Bestor T, Bhagwat AS, Bickle TA, Bitinaite J, Blumenthal RM, Degtyarev S, Dryden DT, Dybvig K et al (2003) A nomenclature for restriction enzymes, DNA methyltransferases, homing endonucleases and their genes. Nucleic Acids Res 31:1805–1812

    PubMed  CAS  Google Scholar 

  7. Lambowitz AM, Zimmerly S (2004) Mobile group II introns. Annu Rev Genet 38:1–35

    PubMed  CAS  Google Scholar 

  8. Choulika A, Perrin A, Dujon B, Nicolas JF (1995) Induction of homologous recombination in mammalian chromosomes by using the I-SceI system of Saccharomyces cerevisiae. Mol Cell Biol 15:1968–1973

    PubMed  CAS  Google Scholar 

  9. Stoddard BL (2005) Homing endonuclease structure and function. Q Rev Biophys 38:49–95

    PubMed  CAS  Google Scholar 

  10. Dassa B, London N, Stoddard BL, Schueler-Furman O, Pietrokovski S (2009) Fractured genes: a novel genomic arrangement involving new split inteins and a new homing endonuclease family. Nucleic Acids Res 37:2560–2573. doi:gkp095[pii]10.1093/nar/gkp095

    PubMed  CAS  Google Scholar 

  11. Tsutakawa SE, Morikawa K (2001) The structural basis of damaged DNA recognition and endonucleolytic cleavage for very short patch repair endonuclease. Nucleic Acids Res 29:3775–3783

    PubMed  CAS  Google Scholar 

  12. Dalgaard JZ, Klar AJ, Moser MJ, Holley WR, Chatterjee A, Mian IS (1997) Statistical modeling and analysis of the LAGLIDADG family of site-specific endonucleases and identification of an intein that encodes a site-specific endonuclease of the HNH family. Nucleic Acids Res 25:4626–4638. doi:gka746[pii]

    PubMed  CAS  Google Scholar 

  13. Chevalier B, Turmel M, Lemieux C, Monnat RJ Jr, Stoddard BL (2003) Flexible DNA target site recognition by divergent homing endonuclease isoschizomers I-CreI and I-MsoI. J Mol Biol 329:253–269

    PubMed  CAS  Google Scholar 

  14. Thompson AJ, Yuan X, Kudlicki W, Herrin DL (1992) Cleavage and recognition pattern of a double-strand-specific endonuclease (I-creI) encoded by the chloroplast 23S rRNA intron of Chlamydomonas reinhardtii. Gene 119:247–251. doi:0378-1119(92)90278-W[pii]

    PubMed  CAS  Google Scholar 

  15. Turmel M, Otis C, Cote V, Lemieux C (1997) Evolutionarily conserved and functionally important residues in the I-CeuI homing endonuclease. Nucleic Acids Res 25:2610–2619

    PubMed  CAS  Google Scholar 

  16. Wang J, Kim HH, Yuan X, Herrin DL (1997) Purification, biochemical characterization and protein-DNA interactions of the I-CreI endonuclease produced in Escherichia coli. Nucleic Acids Res 25:3767–3776

    PubMed  CAS  Google Scholar 

  17. Aagaard C, Awayez MJ, Garrett RA (1997) Profile of the DNA recognition site of the archaeal homing endonuclease I-DmoI. Nucleic Acids Res 25:1523–1530

    PubMed  CAS  Google Scholar 

  18. Bolduc JM, Spiegel PC, Chatterjee P, Brady KL, Downing ME, Caprara MG, Waring RB, Stoddard BL (2003) Structural and biochemical analyses of DNA and RNA binding by a bifunctional homing endonuclease and group I intron splicing factor. Genes Dev 17:2875–2888

    PubMed  CAS  Google Scholar 

  19. Moure CM, Gimble FS, Quiocho FA (2003) The crystal structure of the gene targeting homing endonuclease I-SceI reveals the origins of its target site specificity. J Mol Biol 334:685–695. doi:S0022283603012233[pii]

    PubMed  CAS  Google Scholar 

  20. Chevalier B, Sussman D, Otis C, Noel AJ, Turmel M, Lemieux C, Stephens K, Monnat RJ Jr, Stoddard BL (2004) Metal-dependent DNA cleavage mechanism of the I-CreI LAGLIDADG homing endonuclease. Biochemistry 43:14015–14026

    PubMed  CAS  Google Scholar 

  21. Jurica MS, Monnat RJ Jr, Stoddard BL (1998) DNA recognition and cleavage by the LAGLIDADG homing endonuclease I-CreI. Mol Cell 2:469–476

    PubMed  CAS  Google Scholar 

  22. Marcaida MJ, Prieto J, Redondo P, Nadra AD, Alibes A, Serrano L, Grizot S, Duchateau P, Paques F, Blanco FJ et al (2008) Crystal structure of I-DmoI in complex with its target DNA provides new insights into meganuclease engineering. Proc Natl Acad Sci USA 105:16888–16893. doi:0804795105[pii]10.1073/pnas.0804795105

    PubMed  CAS  Google Scholar 

  23. Moure CM, Gimble FS, Quiocho FA (2002) Crystal structure of the intein homing endonuclease PI-SceI bound to its recognition sequence. Nat Struct Biol 9:764–770

    PubMed  CAS  Google Scholar 

  24. Spiegel PC, Chevalier B, Sussman D, Turmel M, Lemieux C, Stoddard BL (2006) The structure of I-CeuI homing endonuclease: evolving asymmetric DNA recognition from a symmetric protein scaffold. Structure 14:869–880

    PubMed  CAS  Google Scholar 

  25. Chevalier BS, Kortemme T, Chadsey MS, Baker D, Monnat RJ, Stoddard BL (2002) Design, activity, and structure of a highly specific artificial endonuclease. Mol Cell 10:895–905. doi:S1097276502006901[pii]

    PubMed  CAS  Google Scholar 

  26. Epinat JC, Arnould S, Chames P, Rochaix P, Desfontaines D, Puzin C, Patin A, Zanghellini A, Paques F, Lacroix E (2003) A novel engineered meganuclease induces homologous recombination in yeast and mammalian cells. Nucleic Acids Res 31:2952–2962

    PubMed  CAS  Google Scholar 

  27. Grizot S, Smith J, Prieto J, Daboussi F, Redondo P, Merino N, Villate M, Thomas S, Lemaire L, Montoya G, et al. (2009) Efficient targeting of a SCID gene by an engineered single chain homing endonuclease. Nucleic Acids Res (in press)

  28. Steitz TA, Steitz JA (1993) A general two-metal-ion mechanism for catalytic RNA. Proc Natl Acad Sci USA 90:6498–6502

    PubMed  CAS  Google Scholar 

  29. Kostrewa D, Winkler FK (1995) Mg2 + binding to the active site of EcoRV endonuclease: a crystallographic study of complexes with substrate and product DNA at 2 A resolution. Biochemistry 34:683–696

    PubMed  CAS  Google Scholar 

  30. Viadiu H, Aggarwal AK (1998) The role of metals in catalysis by the restriction endonuclease BamHI. Nat Struct Biol 5:910–916. doi:10.1038/2352

    PubMed  CAS  Google Scholar 

  31. Chevalier BS, Monnat RJ Jr, Stoddard BL (2001) The homing endonuclease I-CreI uses three metals, one of which is shared between the two active sites. Nat Struct Biol 8:312–316

    PubMed  CAS  Google Scholar 

  32. Moure CM, Gimble FS, Quiocho FA (2008) Crystal structures of I-SceI complexed to nicked DNA substrates: snapshots of intermediates along the DNA cleavage reaction pathway. Nucleic Acids Res 36:3287–3296

    PubMed  CAS  Google Scholar 

  33. Ho Y, Kim SJ, Waring RB (1997) A protein encoded by a group I intron in Aspergillus nidulans directly assists RNA splicing and is a DNA endonuclease. Proc Natl Acad Sci USA 94:8994–8999

    PubMed  CAS  Google Scholar 

  34. Ho Y, Waring RB (1999) The maturase encoded by a group I intron from Aspergillus nidulans stabilizes RNA tertiary structure and promotes rapid splicing. J Mol Biol 292:987–1001. doi:10.1006/jmbi.1999.3070S0022-2836(99)93070-X[pii]

    PubMed  CAS  Google Scholar 

  35. Arnould S, Perez C, Cabaniols JP, Smith J, Gouble A, Grizot S, Epinat JC, Duclert A, Duchateau P, Paques F (2007) Engineered I-CreI derivatives cleaving sequences from the human XPC gene can induce highly efficient gene correction in mammalian cells. J Mol Biol 371:49–65

    PubMed  CAS  Google Scholar 

  36. Arnould S, Chames P, Perez C, Lacroix E, Duclert A, Epinat JC, Stricher F, Petit AS, Patin A, Guillier S et al (2006) Engineering of large numbers of highly specific homing endonucleases that induce recombination on novel DNA targets. J Mol Biol 355:443–458. doi:S0022-2836(05)01325-2[pii]10.1016/j.jmb.2005.10.065

    PubMed  CAS  Google Scholar 

  37. Smith J, Grizot S, Arnould S, Duclert A, Epinat JC, Chames P, Prieto J, Redondo P, Blanco FJ, Bravo J et al (2006) A combinatorial approach to create artificial homing endonucleases cleaving chosen sequences. Nucleic Acids Res 34:e149. doi:gkl720[pii]10.1093/nar/gkl720

    PubMed  Google Scholar 

  38. Redondo P, Prieto J, Munoz IG, Alibes A, Stricher F, Serrano L, Cabaniols JP, Daboussi F, Arnould S, Perez C et al (2008) Molecular basis of xeroderma pigmentosum group C DNA recognition by engineered meganucleases. Nature 456:107–111

    PubMed  CAS  Google Scholar 

  39. Friedhoff P, Franke I, Meiss G, Wende W, Krause KL, Pingoud A (1999) A similar active site for non-specific and specific endonucleases. Nat Struct Biol 6:112–113. doi:10.1038/5796

    PubMed  CAS  Google Scholar 

  40. Kuhlmann UC, Moore GR, James R, Kleanthous C, Hemmings AM (1999) Structural parsimony in endonuclease active sites: should the number of homing endonuclease families be redefined? FEBS Lett 463:1–2. doi:S0014-5793(99)01499-4[pii]

    PubMed  CAS  Google Scholar 

  41. Mehta P, Katta K, Krishnaswamy S (2004) HNH family subclassification leads to identification of commonality in the His-Me endonuclease superfamily. Protein Sci 13:295–300. doi:10.1110/ps.03115604

    PubMed  CAS  Google Scholar 

  42. Jakubauskas A, Giedriene J, Bujnicki JM, Janulaitis A (2007) Identification of a single HNH active site in type IIS restriction endonuclease Eco31I. J Mol Biol 370:157–169. doi:S0022-2836(07)00541-4[pii]10.1016/j.jmb.2007.04.049

    PubMed  CAS  Google Scholar 

  43. Azarinskas A, Maneliene Z, Jakubauskas A (2006) Hin4II, a new prototype restriction endonuclease from Haemophilus influenzae RFL4: discovery, cloning and expression in Escherichia coli. J Biotechnol 123:288–296. doi:S0168-1656(05)00789-3[pii]10.1016/j.jbiotec.2005.12.016

    PubMed  CAS  Google Scholar 

  44. Saravanan M, Vasu K, Kanakaraj R, Rao DN, Nagaraja V (2007) R.KpnI, an HNH superfamily REase, exhibits differential discrimination at non-canonical sequences in the presence of Ca2 + and Mg2+. Nucleic Acids Res 35:2777–2786. doi:gkm114[pii]10.1093/nar/gkm114

    PubMed  CAS  Google Scholar 

  45. Cymerman IA, Obarska A, Skowronek KJ, Lubys A, Bujnicki JM (2006) Identification of a new subfamily of HNH nucleases and experimental characterization of a representative member, HphI restriction endonuclease. Proteins 65:867–876. doi:10.1002/prot.21156

    PubMed  CAS  Google Scholar 

  46. Chevalier BS, Stoddard BL (2001) Homing endonucleases: structural and functional insight into the catalysts of intron/intein mobility. Nucleic Acids Res 29:3757–3774

    PubMed  CAS  Google Scholar 

  47. Goodrich-Blair H, Scarlato V, Gott JM, Xu MQ, Shub DA (1990) A self-splicing group I intron in the DNA polymerase gene of Bacillus subtilis bacteriophage SPO1. Cell 63:417–424. doi:0092-8674(90)90174-D[pii]

    PubMed  CAS  Google Scholar 

  48. Goodrich-Blair H, Shub DA (1994) The DNA polymerase genes of several HMU-bacteriophages have similar group I introns with highly divergent open reading frames. Nucleic Acids Res 22:3715–3721

    PubMed  CAS  Google Scholar 

  49. Goodrich-Blair H, Shub DA (1996) Beyond homing: competition between intron endonucleases confers a selective advantage on flanking genetic markers. Cell 84:211–221. doi:S0092-8674(00)80976-9[pii]

    PubMed  CAS  Google Scholar 

  50. Landthaler M, Lau NC, Shub DA (2004) Group I intron homing in Bacillus phages SPO1 and SP82: a gene conversion event initiated by a nicking homing endonuclease. J Bacteriol 186:4307–4314. doi:10.1128/JB.186.13.4307-4314.2004186/13/4307[pii]

    PubMed  CAS  Google Scholar 

  51. Landthaler M, Shub DA (2003) The nicking homing endonuclease I-BasI is encoded by a group I intron in the DNA polymerase gene of the Bacillus thuringiensis phage Bastille. Nucleic Acids Res 31:3071–3077

    PubMed  CAS  Google Scholar 

  52. Eddy SR, Gold L (1991) The phage T4 nrdB intron: a deletion mutant of a version found in the wild. Genes Dev 5:1032–1041

    PubMed  CAS  Google Scholar 

  53. Drouin M, Lucas P, Otis C, Lemieux C, Turmel M (2000) Biochemical characterization of I-CmoeI reveals that this H-N-H homing endonuclease shares functional similarities with H-N-H colicins. Nucleic Acids Res 28:4566–4572

    PubMed  CAS  Google Scholar 

  54. Holloway SP, Deshpande NN, Herrin DL (1999) The catalytic group-I introns of the psbA gene of chlamydomonas reinhardtii : core structures, ORFs and evolutionary implications. Curr Genet 36:69–78. doi:90360069.294[pii]

    PubMed  CAS  Google Scholar 

  55. Shen BW, Landthaler M, Shub DA, Stoddard BL (2004) DNA binding and cleavage by the HNH homing endonuclease I-HmuI. J Mol Biol 342:43–56

    PubMed  CAS  Google Scholar 

  56. Johansen S, Embley TM, Willassen NP (1993) A family of nuclear homing endonucleases. Nucleic Acids Res 21:4405

    PubMed  CAS  Google Scholar 

  57. Muscarella DE, Vogt VM (1993) A mobile group I intron from Physarum polycephalum can insert itself and induce point mutations in the nuclear ribosomal DNA of saccharomyces cerevisiae. Mol Cell Biol 13:1023–1033

    PubMed  CAS  Google Scholar 

  58. Muscarella DE, Ellison EL, Ruoff BM, Vogt VM (1990) Characterization of I-Ppo, an intron-encoded endonuclease that mediates homing of a group I intron in the ribosomal DNA of Physarum polycephalum. Mol Cell Biol 10:3386–3396

    PubMed  CAS  Google Scholar 

  59. Wittmayer PK, Raines RT (1996) Substrate binding and turnover by the highly specific I-PpoI endonuclease. Biochemistry 35:1076–1083. doi:10.1021/bi952363vbi952363v[pii]

    PubMed  CAS  Google Scholar 

  60. Wittmayer PK, McKenzie JL, Raines RT (1998) Degenerate DNA recognition by I-PpoI endonuclease. Gene 206:11–21. doi:S0378111997005635[pii]

    PubMed  CAS  Google Scholar 

  61. Johansen S, Vogt VM (1994) An intron in the nuclear ribosomal DNA of Didymium iridis codes for a group I ribozyme and a novel ribozyme that cooperate in self-splicing. Cell 76:725–734. doi:0092-8674(94)90511-8[pii]

    PubMed  CAS  Google Scholar 

  62. Johansen S, Elde M, Vader A, Haugen P, Haugli K, Haugli F (1997) In vivo mobility of a group I twintron in nuclear ribosomal DNA of the myxomycete Didymium iridis. Mol Microbiol 24:737–745

    PubMed  CAS  Google Scholar 

  63. Haugen P, Wikmark OG, Vader A, Coucheron DH, Sjottem E, Johansen SD (2005) The recent transfer of a homing endonuclease gene. Nucleic Acids Res 33:2734–2741

    PubMed  CAS  Google Scholar 

  64. Johansen SD, Haugen P, Nielsen H (2007) Expression of protein-coding genes embedded in ribosomal DNA. Biol Chem 388:679–686. doi:10.1515/BC.2007.089

    PubMed  CAS  Google Scholar 

  65. Elde M, Haugen P, Willassen NP, Johansen S (1999) I-NjaI, a nuclear intron-encoded homing endonuclease from Naegleria, generates a pentanucleotide 3’ cleavage-overhang within a 19 base-pair partially symmetric DNA recognition site. Eur J Biochem 259:281–288

    PubMed  CAS  Google Scholar 

  66. Elde M, Willassen NP, Johansen S (2000) Functional characterization of isoschizomeric His-Cys box homing endonucleases from Naegleria. Eur J Biochem 267:7257–7266. doi:ejb1862[pii]

    PubMed  CAS  Google Scholar 

  67. Ellison EL, Vogt VM (1993) Interaction of the intron-encoded mobility endonuclease I-PpoI with its target site. Mol Cell Biol 13:7531–7539

    PubMed  CAS  Google Scholar 

  68. Flick KE, Jurica MS, Monnat RJ Jr, Stoddard BL (1998) DNA binding and cleavage by the nuclear intron-encoded homing endonuclease I-PpoI. Nature 394:96–101

    PubMed  CAS  Google Scholar 

  69. Flick KE, McHugh D, Heath JD, Stephens KM, Monnat RJ Jr, Stoddard BL (1997) Crystallization and preliminary X-ray studies of I-PpoI: a nuclear, intron-encoded homing endonuclease from Physarum polycephalum. Protein Sci 6:2677–2680

    PubMed  CAS  Google Scholar 

  70. Galburt EA, Chevalier B, Tang W, Jurica MS, Flick KE, Monnat RJ Jr, Stoddard BL (1999) A novel endonuclease mechanism directly visualized for I-PpoI. Nat Struct Biol 6:1096–1099. doi:10.1038/70027

    PubMed  CAS  Google Scholar 

  71. Galburt EA, Chadsey MS, Jurica MS, Chevalier BS, Erho D, Tang W, Monnat RJ Jr, Stoddard BL (2000) Conformational changes and cleavage by the homing endonuclease I-PpoI: a critical role for a leucine residue in the active site. J Mol Biol 300:877–887

    PubMed  CAS  Google Scholar 

  72. Eastberg JH, Eklund J, Monnat R Jr, Stoddard BL (2007) Mutability of an HNH nuclease imidazole general base and exchange of a deprotonation mechanism. Biochemistry 46:7215–7225. doi:10.1021/bi700418d

    PubMed  CAS  Google Scholar 

  73. Eklund JL, Ulge UY, Eastberg J, Monnat RJ Jr (2007) Altered target site specificity variants of the I-PpoI His-Cys box homing endonuclease. Nucleic Acids Res 35:5839–5850. doi:gkm624[pii]10.1093/nar/gkm624

    PubMed  CAS  Google Scholar 

  74. Dunin-Horkawicz S, Feder M, Bujnicki JM (2006) Phylogenomic analysis of the GIY-YIG nuclease superfamily. BMC Genomics 7:98. doi:1471-2164-7-98[pii]10.1186/1471-2164-7-98

    PubMed  Google Scholar 

  75. Kowalski JC, Belfort M, Stapleton MA, Holpert M, Dansereau JT, Pietrokovski S, Baxter SM, Derbyshire V (1999) Configuration of the catalytic GIY-YIG domain of intron endonuclease I-TevI: coincidence of computational and molecular findings. Nucleic Acids Res 27:2115–2125. doi:gkc361[pii]

    PubMed  CAS  Google Scholar 

  76. Nord D, Sjoberg BM (2008) Unconventional GIY-YIG homing endonuclease encoded in group I introns in closely related strains of the Bacillus cereus group. Nucleic Acids Res 36:300–310. doi:gkm1016[pii]10.1093/nar/gkm1016

    PubMed  CAS  Google Scholar 

  77. Derbyshire V, Kowalski JC, Dansereau JT, Hauer CR, Belfort M (1997) Two-domain structure of the td intron-encoded endonuclease I-TevI correlates with the two-domain configuration of the homing site. J Mol Biol 265:494–506

    PubMed  CAS  Google Scholar 

  78. Bujnicki JM, Rotkiewicz P, Kolinski A, Rychlewski L (2001) Three-dimensional modeling of the I-TevI homing endonuclease catalytic domain, a GIY-YIG superfamily member, using NMR restraints and Monte Carlo dynamics. Protein Eng 14:717–721

    PubMed  CAS  Google Scholar 

  79. Liu Q, Derbyshire V, Belfort M, Edgell DR (2006) Distance determination by GIY-YIG intron endonucleases: discrimination between repression and cleavage functions. Nucleic Acids Res 34:1755–1764. doi:34/6/1755[pii]10.1093/nar/gkl079

    PubMed  CAS  Google Scholar 

  80. Van Roey P, Meehan L, Kowalski JC, Belfort M, Derbyshire V (2002) Catalytic domain structure and hypothesis for function of GIY-YIG intron endonuclease I-TevI. Nat Struct Biol 9:806–811. doi:10.1038/nsb853nsb853[pii]

    PubMed  Google Scholar 

  81. Sitbon E, Pietrokovski S (2003) New types of conserved sequence domains in DNA-binding regions of homing endonucleases. Trends Biochem Sci 28:473–477. doi:S0968000403001701[pii]

    PubMed  CAS  Google Scholar 

  82. Dean AB, Stanger MJ, Dansereau JT, Van Roey P, Derbyshire V, Belfort M (2002) Zinc finger as distance determinant in the flexible linker of intron endonuclease I-TevI. Proc Natl Acad Sci USA 99:8554–8561. doi:10.1073/pnas.082253699082253699[pii]

    PubMed  CAS  Google Scholar 

  83. Liu Q, Dansereau JT, Puttamadappa SS, Shekhtman A, Derbyshire V, Belfort M (2008) Role of the interdomain linker in distance determination for remote cleavage by homing endonuclease I-TevI. J Mol Biol 379:1094–1106. doi:S0022-2836(08)00493-2[pii]10.1016/j.jmb.2008.04.047

    PubMed  CAS  Google Scholar 

  84. Brok-Volchanskaya VS, Kadyrov FA, Sivogrivov DE, Kolosov PM, Sokolov AS, Shlyapnikov MG, Kryukov VM, Granovsky IE (2008) Phage T4 SegB protein is a homing endonuclease required for the preferred inheritance of T4 tRNA gene region occurring in co-infection with a related phage. Nucleic Acids Res 36:2094–2105. doi:gkn053[pii]10.1093/nar/gkn053

    PubMed  CAS  Google Scholar 

  85. Carter JM, Friedrich NC, Kleinstiver B, Edgell DR (2007) Strand-specific contacts and divalent metal ion regulate double-strand break formation by the GIY-YIG homing endonuclease I-BmoI. J Mol Biol 374:306–321. doi:S0022-2836(07)01202-8[pii]10.1016/j.jmb.2007.09.027

    PubMed  CAS  Google Scholar 

  86. Bryk M, Quirk SM, Mueller JE, Loizos N, Lawrence C, Belfort M (1993) The td intron endonuclease I-TevI makes extensive sequence-tolerant contacts across the minor groove of its DNA target. EMBO J 12:4040–4041

    PubMed  CAS  Google Scholar 

  87. Mueller JE, Smith D, Bryk M, Belfort M (1995) Intron-encoded endonuclease I-TevI binds as a monomer to effect sequential cleavage via conformational changes in the td homing site. EMBO J 14:5724–5735

    PubMed  CAS  Google Scholar 

  88. Ibryashkina EM, Sasnauskas G, Solonin AS, Zakharova MV, Siksnys V (2009) Oligomeric structure diversity within the GIY-YIG nuclease family. J Mol Biol 387:10–16. doi:S0022-2836(09)00098-9[pii]10.1016/j.jmb.2009.01.048

    PubMed  CAS  Google Scholar 

  89. Chu FK, Maley G, Pedersen-Lane J, Wang AM, Maley F (1990) Characterization of the restriction site of a prokaryotic intron-encoded endonuclease. Proc Natl Acad Sci USA 87:3574–3578

    PubMed  CAS  Google Scholar 

  90. Bell-Pedersen D, Quirk SM, Bryk M, Belfort M (1991) I-TevI, the endonuclease encoded by the mobile td intron, recognizes binding and cleavage domains on its DNA target. Proc Natl Acad Sci USA 88:7719–7723

    PubMed  CAS  Google Scholar 

  91. Van Roey P, Waddling CA, Fox KM, Belfort M, Derbyshire V (2001) Intertwined structure of the DNA-binding domain of intron endonuclease I-TevI with its substrate. EMBO J 20:3631–3637. doi:10.1093/emboj/20.14.3631

    PubMed  Google Scholar 

  92. Edgell DR, Shub DA (2001) Related homing endonucleases I-BmoI and I-TevI use different strategies to cleave homologous recognition sites. Proc Natl Acad Sci USA 98:7898–7903. doi:10.1073/pnas.141222498141222498[pii]

    PubMed  CAS  Google Scholar 

  93. Bryk M, Belisle M, Mueller JE, Belfort M (1995) Selection of a remote cleavage site by I-tevI, the td intron-encoded endonuclease. J Mol Biol 247:197–210. doi:S0022-2836(84)70133-1[pii]10.1006/jmbi.1994.0133

    PubMed  CAS  Google Scholar 

  94. Edgell DR, Stanger MJ, Belfort M (2004) Coincidence of cleavage sites of intron endonuclease I-TevI and critical sequences of the host thymidylate synthase gene. J Mol Biol 343:1231–1241. doi:S0022-2836(04)01120-9[pii]10.1016/j.jmb.2004.09.005

    PubMed  CAS  Google Scholar 

  95. Bonocora RP, Shub DA (2001) A novel group I intron-encoded endonuclease specific for the anticodon region of tRNA(fMet) genes. Mol Microbiol 39:1299–1306. doi:mmi2318[pii]

    PubMed  CAS  Google Scholar 

  96. Biniszkiewicz D, Cesnaviciene E, Shub DA (1994) Self-splicing group I intron in cyanobacterial initiator methionine tRNA: evidence for lateral transfer of introns in bacteria. EMBO J 13:4629–4635

    PubMed  CAS  Google Scholar 

  97. Zhao L, Bonocora RP, Shub DA, Stoddard BL (2007) The restriction fold turns to the dark side: a bacterial homing endonuclease with a PD-(D/E)-XK motif. EMBO J 26:2432–2442. doi:7601672[pii]10.1038/sj.emboj.7601672

    PubMed  CAS  Google Scholar 

  98. Orlowski J, Boniecki M, Bujnicki JM (2007) I-Ssp6803I: the first homing endonuclease from the PD-(D/E)XK superfamily exhibits an unusual mode of DNA recognition. Bioinformatics 23:527–530. doi:btm007[pii]10.1093/bioinformatics/btm007

    PubMed  CAS  Google Scholar 

  99. Zhao L, Pellenz S, Stoddard BL (2009) Activity and specificity of the bacterial PD-(D/E)XK homing endonuclease I-Ssp6803I. J Mol Biol 385:1498–1510. doi:S0022-2836(08)01406-X[pii]10.1016/j.jmb.2008.10.096

    PubMed  CAS  Google Scholar 

  100. Szostak JW, Orr-Weaver TL, Rothstein RJ, Stahl FW (1983) The double-strand-break repair model for recombination. Cell 33:25–35

    PubMed  CAS  Google Scholar 

  101. Sung P, Klein H (2006) Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol 7:739–750

    PubMed  CAS  Google Scholar 

  102. Brugmans L, Kanaar R, Essers J (2007) Analysis of DNA double-strand break repair pathways in mice. Mutat Res 614:95–108

    PubMed  CAS  Google Scholar 

  103. Paques F, Haber JE (1999) Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 63:349–404

    PubMed  CAS  Google Scholar 

  104. van Gent DC, Hoeijmakers JH, Kanaar R (2001) Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2:196–206

    PubMed  Google Scholar 

  105. Mimitou EP, Symington LS (2009) Nucleases and helicases take center stage in homologous recombination. Trends Biochem Sci 34:264–272

    PubMed  CAS  Google Scholar 

  106. Lee GS, Neiditch MB, Salus SS, Roth DB (2004) RAG proteins shepherd double-strand breaks to a specific pathway, suppressing error-prone repair, but RAG nicking initiates homologous recombination. Cell 117:171–184

    PubMed  CAS  Google Scholar 

  107. McConnell Smith A, Takeuchi R, Pellenz S, Davis L, Maizels N, Monnat RJ Jr, Stoddard BL (2009) Generation of a nicking enzyme that stimulates site-specific gene conversion from the I-AniI LAGLIDADG homing endonuclease. Proc Natl Acad Sci USA 106:5099–5104

    PubMed  CAS  Google Scholar 

  108. Fortini P, Dogliotti E (2007) Base damage and single-strand break repair: mechanisms and functional significance of short- and long-patch repair subpathways. DNA Repair (Amst) 6:398–409. doi:S1568-7864(06)00317-X[pii]10.1016/j.dnarep.2006.10.008

    CAS  Google Scholar 

  109. Dianov GL, Parsons JL (2007) Co-ordination of DNA single strand break repair. DNA Repair (Amst) 6:454–460. doi:S1568-7864(06)00318-1[pii]10.1016/j.dnarep.2006.10.009

    CAS  Google Scholar 

  110. Caldecott KW (2008) Single-strand break repair and genetic disease. Nat Rev Genet 9:619–631. doi:nrg2380[pii]10.1038/nrg2380

    PubMed  CAS  Google Scholar 

  111. Johnson RD, Jasin M (2001) Double-strand-break-induced homologous recombination in mammalian cells. Biochem Soc Trans 29:196–201

    PubMed  CAS  Google Scholar 

  112. Rimseliene R, Maneliene Z, Lubys A, Janulaitis A (2003) Engineering of restriction endonucleases: using methylation activity of the bifunctional endonuclease Eco57I to select the mutant with a novel sequence specificity. J Mol Biol 327:383–391

    PubMed  CAS  Google Scholar 

  113. Voziyanov Y, Konieczka JH, Stewart AF, Jayaram M (2003) Stepwise manipulation of DNA specificity in Flp recombinase: progressively adapting Flp to individual and combinatorial mutations in its target site. J Mol Biol 326:65–76

    PubMed  CAS  Google Scholar 

  114. Durai S, Mani M, Kandavelou K, Wu J, Porteus MH, Chandrasegaran S (2005) Zinc finger nucleases: custom-designed molecular scissors for genome engineering of plant and mammalian cells. Nucleic Acids Res 33:5978–5990

    PubMed  CAS  Google Scholar 

  115. Porteus MH, Carroll D (2005) Gene targeting using zinc finger nucleases. Nat Biotechnol 23:967–973

    PubMed  CAS  Google Scholar 

  116. Bibikova M, Beumer K, Trautman JK, Carroll D (2003) Enhancing gene targeting with designed zinc finger nucleases. Science 300:764

    PubMed  CAS  Google Scholar 

  117. Porteus MH, Baltimore D (2003) Chimeric nucleases stimulate gene targeting in human cells. Science 300:763

    PubMed  Google Scholar 

  118. Alwin S, Gere MB, Guhl E, Effertz K, Barbas CF 3rd, Segal DJ, Weitzman MD, Cathomen T (2005) Custom zinc-finger nucleases for use in human cells. Mol Ther 12:610–617

    PubMed  CAS  Google Scholar 

  119. Porteus MH (2006) Mammalian gene targeting with designed zinc finger nucleases. Mol Ther 13:438–446

    PubMed  CAS  Google Scholar 

  120. Wright DA, Townsend JA, Winfrey RJ Jr, Irwin PA, Rajagopal J, Lonosky PM, Hall BD, Jondle MD, Voytas DF (2005) High-frequency homologous recombination in plants mediated by zinc-finger nucleases. Plant J 44:693–705

    PubMed  CAS  Google Scholar 

  121. Urnov FD, Miller JC, Lee YL, Beausejour CM, Rock JM, Augustus S, Jamieson AC, Porteus MH, Gregory PD, Holmes MC (2005) Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 435:646–651

    PubMed  CAS  Google Scholar 

  122. Szczepek M, Brondani V, Buchel J, Serrano L, Segal DJ, Cathomen T (2007) Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases. Nat Biotechnol 25:786–793

    PubMed  CAS  Google Scholar 

  123. Seligman LM, Stephens KM, Savage JH, Monnat RJ Jr (1997) Genetic analysis of the Chlamydomonas reinhardtii I-CreI mobile intron homing system in Escherichia coli. Genetics 147:1653–1664

    PubMed  CAS  Google Scholar 

  124. Paques F, Duchateau P (2007) Meganucleases and DNA double-strand break-induced recombination: perspectives for gene therapy. Curr Gene Ther 7:49–66

    PubMed  CAS  Google Scholar 

  125. Doyon JB, Pattanayak V, Meyer CB, Liu DR (2006) Directed evolution and substrate specificity profile of homing endonuclease I-SceI. J Am Chem Soc 128:2477–2484

    PubMed  CAS  Google Scholar 

  126. Chames P, Epinat JC, Guillier S, Patin A, Lacroix E, Paques F (2005) In vivo selection of engineered homing endonucleases using double-strand break induced homologous recombination. Nucleic Acids Res 33:e178

    PubMed  Google Scholar 

  127. Chica RA, Doucet N, Pelletier JN (2005) Semi-rational approaches to engineering enzyme activity: combining the benefits of directed evolution and rational design. Curr Opin Biotechnol 16:378–384

    PubMed  CAS  Google Scholar 

  128. Ashworth J, Havranek JJ, Duarte CM, Sussman D, Monnat RJ Jr, Stoddard BL, Baker D (2006) Computational redesign of endonuclease DNA binding and cleavage specificity. Nature 441:656–659

    PubMed  CAS  Google Scholar 

  129. Stary A, Sarasin A (2002) The genetics of the hereditary xeroderma pigmentosum syndrome. Biochimie 84:49–60

    PubMed  CAS  Google Scholar 

  130. Cleaver JE (2005) Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer 5:564–573

    PubMed  CAS  Google Scholar 

  131. Aslan G, Karacal N, Gorgu M (1999) New tumor formation on split-thickness skin grafted areas in xeroderma pigmentosum. Ann Plast Surg 43:657–660

    PubMed  CAS  Google Scholar 

  132. Sonmez Ergun S (2003) Resurfacing the dorsum of the hand in a patient with Xeroderma pigmentosum. Dermatol Surg 29:782–784

    PubMed  Google Scholar 

  133. Asselineau D, Bernhard B, Bailly C, Darmon M (1985) Epidermal morphogenesis and induction of the 67 kD keratin polypeptide by culture of human keratinocytes at the liquid-air interface. Exp Cell Res 159:536–539

    PubMed  CAS  Google Scholar 

  134. Arnaudeau-Begard C, Brellier F, Chevallier-Lagente O, Hoeijmakers J, Bernerd F, Sarasin A, Magnaldo T (2003) Genetic correction of DNA repair-deficient/cancer-prone xeroderma pigmentosum group C keratinocytes. Hum Gene Ther 14:983–996

    PubMed  CAS  Google Scholar 

  135. Smih F, Rouet P, Romanienko PJ, Jasin M (1995) Double-strand breaks at the target locus stimulate gene targeting in embryonic stem cells. Nucleic Acids Res 23:5012–5019

    PubMed  CAS  Google Scholar 

  136. Rothkamm K, Kruger I, Thompson LH, Lobrich M (2003) Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol 23:5706–5715

    PubMed  CAS  Google Scholar 

  137. Sonoda E, Hochegger H, Saberi A, Taniguchi Y, Takeda S (2006) Differential usage of non-homologous end-joining and homologous recombination in double strand break repair. DNA Repair (Amst) 5:1021–1029

    CAS  Google Scholar 

  138. Pierce AJ, Hu P, Han M, Ellis N, Jasin M (2001) Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev 15:3237–3242

    PubMed  CAS  Google Scholar 

  139. Yanez RJ, Porter AC (2002) Differential effects of Rad52p overexpression on gene targeting and extrachromosomal homologous recombination in a human cell line. Nucleic Acids Res 30:740–748

    PubMed  CAS  Google Scholar 

  140. Di Primio C, Galli A, Cervelli T, Zoppe M, Rainaldi G (2005) Potentiation of gene targeting in human cells by expression of Saccharomyces cerevisiae Rad52. Nucleic Acids Res 33:4639–4648

    PubMed  CAS  Google Scholar 

  141. Shaked H, Melamed-Bessudo C, Levy AA (2005) High-frequency gene targeting in Arabidopsis plants expressing the yeast RAD54 gene. Proc Natl Acad Sci USA 102:12265–12269

    PubMed  CAS  Google Scholar 

  142. Saberi A, Hochegger H, Szuts D, Lan L, Yasui A, Sale JE, Taniguchi Y, Murakawa Y, Zeng W, Yokomori K et al (2007) RAD18 and poly(ADP-ribose) polymerase independently suppress the access of nonhomologous end joining to double-strand breaks and facilitate homologous recombination-mediated repair. Mol Cell Biol 27:2562–2571

    PubMed  CAS  Google Scholar 

  143. Elliott B, Richardson C, Winderbaum J, Nickoloff JA, Jasin M (1998) Gene conversion tracts from double-strand break repair in mammalian cells. Mol Cell Biol 18:93–101

    PubMed  CAS  Google Scholar 

  144. Donoho G, Jasin M, Berg P (1998) Analysis of gene targeting and intrachromosomal homologous recombination stimulated by genomic double-strand breaks in mouse embryonic stem cells. Mol Cell Biol 18:4070–4078

    PubMed  CAS  Google Scholar 

  145. Townsend JA, Wright DA, Winfrey RJ, Fu F, Maeder ML, Joung JK, Voytas DF (2009) High-frequency modification of plant genes using engineered zinc-finger nucleases. Nature 459:442–445. doi:nature07845[pii]10.1038/nature07845

    PubMed  CAS  Google Scholar 

  146. Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, Trauger S, Bien G, Yao S, Zhu Y et al (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4:381–384

    PubMed  CAS  Google Scholar 

  147. Muller-Sieburg CE, Cho RH, Thoman M, Adkins B, Sieburg HB (2002) Deterministic regulation of hematopoietic stem cell self-renewal and differentiation. Blood 100:1302–1309

    PubMed  CAS  Google Scholar 

  148. Cutler C, Antin JH (2001) Peripheral blood stem cells for allogeneic transplantation: a review. Stem Cells 19:108–117

    PubMed  CAS  Google Scholar 

  149. Copelan EA (2006) Hematopoietic stem-cell transplantation. N Engl J Med 354:1813–1826

    PubMed  CAS  Google Scholar 

  150. Kern S, Eichler H, Stoeve J, Kluter H, Bieback K (2006) Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24:1294–1301

    PubMed  CAS  Google Scholar 

  151. Joerger AC, Fersht AR (2008) Structural biology of the tumor suppressor p53. Annu Rev Biochem 77:557–582

    PubMed  CAS  Google Scholar 

  152. Martins CP, Brown-Swigart L, Evan GI (2006) Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127:1323–1334

    PubMed  CAS  Google Scholar 

  153. Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445:661–665

    PubMed  CAS  Google Scholar 

  154. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419

    PubMed  CAS  Google Scholar 

  155. Fischer A, Abina SH, Thrasher A, von Kalle C, Cavazzana-Calvo M (2004) LMO2 and gene therapy for severe combined immunodeficiency. N Engl J Med 350:2526–2527 author reply

    PubMed  CAS  Google Scholar 

  156. Abbott A (2006) Questions linger about unexplained gene-therapy trial death. Nat Med 12:597

    PubMed  CAS  Google Scholar 

  157. Thrasher AJ, Gaspar HB, Baum C, Modlich U, Schambach A, Candotti F, Otsu M, Sorrentino B, Scobie L, Cameron E et al (2006) Gene therapy: X-SCID transgene leukaemogenicity. Nature 443:E5–E6 discussion E6–E7

    CAS  Google Scholar 

  158. Lehmann K, Schmidt U (2003) Group II introns: structure and catalytic versatility of large natural ribozymes. Crit Rev Biochem Mol Biol 38:249–303

    PubMed  CAS  Google Scholar 

  159. Corneo B, Moshous D, Gungor T, Wulffraat N, Philippet P, Le Deist FL, Fischer A, de Villartay JP (2001) Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. Blood 97:2772–2776

    PubMed  CAS  Google Scholar 

  160. Eastberg JH, McConnell Smith A, Zhao L, Ashworth J, Shen BW, Stoddard BL (2007) Thermodynamics of DNA target site recognition by homing endonucleases. Nucleic Acids Res 35:7209–7221. doi:gkm867[pii]10.1093/nar/gkm867

    PubMed  CAS  Google Scholar 

  161. Heath PJ, Stephens KM, Monnat RJ Jr, Stoddard BL (1997) The structure of I-Crel, a group I intron-encoded homing endonuclease. Nat Struct Biol 4:468–476

    PubMed  CAS  Google Scholar 

  162. Silva GH, Dalgaard JZ, Belfort M, Van Roey P (1999) Crystal structure of the thermostable archaeal intron-encoded endonuclease I-DmoI. J Mol Biol 286:1123–1136

    PubMed  CAS  Google Scholar 

  163. Edgell DR, Derbyshire V, Van Roey P, LaBonne S, Stanger MJ, Li Z, Boyd TM, Shub DA, Belfort M (2004) Intron-encoded homing endonuclease I-TevI also functions as a transcriptional autorepressor. Nat Struct Mol Biol 11:936–944

    PubMed  CAS  Google Scholar 

  164. Seligman LM, Chisholm KM, Chevalier BS, Chadsey MS, Edwards ST, Savage JH, Veillet AL (2002) Mutations altering the cleavage specificity of a homing endonuclease. Nucleic Acids Res 30:3870–3879

    PubMed  CAS  Google Scholar 

  165. Sussman D, Chadsey M, Fauce S, Engel A, Bruett A, Monnat R Jr, Stoddard BL, Seligman LM (2004) Isolation and characterization of new homing endonuclease specificities at individual target site positions. J Mol Biol 342:31–41

    PubMed  CAS  Google Scholar 

  166. Rosen LE, Morrison HA, Masri S, Brown MJ, Springstubb B, Sussman D, Stoddard BL, Seligman LM (2006) Homing endonuclease I-CreI derivatives with novel DNA target specificities. Nucleic Acids Res 34:4791–4800

    PubMed  CAS  Google Scholar 

  167. Gruen M, Chang K, Serbanescu I, Liu DR (2002) An in vivo selection system for homing endonuclease activity. Nucleic Acids Res 30:e29

    PubMed  Google Scholar 

  168. Gimble FS, Moure CM, Posey KL (2003) Assessing the plasticity of DNA target site recognition of the PI-SceI homing endonuclease using a bacterial two-hybrid selection system. J Mol Biol 334:993–1008

    PubMed  CAS  Google Scholar 

  169. Steuer S, Pingoud V, Pingoud A, Wende W (2004) Chimeras of the homing endonuclease PI-SceI and the homologous Candida tropicalis intein: a study to explore the possibility of exchanging DNA-binding modules to obtain highly specific endonucleases with altered specificity. Chembiochem 5:206–213

    PubMed  CAS  Google Scholar 

  170. Silva GH, Belfort M, Wende W, Pingoud A (2006) From monomeric to homodimeric endonucleases and back: engineering novel specificity of LAGLIDADG enzymes. J Mol Biol 361:744–754

    PubMed  CAS  Google Scholar 

  171. Li H, Pellenz S, Ulge U, Stoddard BL, Monnat RJ Jr (2009) Generation of single-chain LAGLIDADG homing endonucleases from native homodimeric precursor proteins. Nucleic Acids Res 37:1650–1662. doi:gkp004[pii]10.1093/nar/gkp004

    PubMed  CAS  Google Scholar 

  172. Fajardo-Sanchez E, Stricher F, Paques F, Isalan M, Serrano L (2008) Computer design of obligate heterodimer meganucleases allows efficient cutting of custom DNA sequences. Nucleic Acids Res 36:2163–2173

    PubMed  CAS  Google Scholar 

  173. Smith JG, Sylvestre, Arnould S, Duclert A, Epinat J-C, Prieto J, Redondo P, Blanco F, Bravo J, Montoya G, Pâques F, Duchateau P (2006) A combinatorial approach to create artificial homing endonucleases cleaving chosen sequences. Nucleic Acids Res

  174. Ulbrichova D, Hrdinka M, Saudek V, Martasek P (2009) Acute intermittent porphyria–impact of mutations found in the hydroxymethylbilane synthase gene on biochemical and enzymatic protein properties. Febs J 276:2106–2115

    PubMed  CAS  Google Scholar 

  175. Wiederholt T, Poblete-Gutierrez P, Gardlo K, Goerz G, Bolsen K, Merk HF, Frank J (2006) Identification of mutations in the uroporphyrinogen III cosynthase gene in German patients with congenital erythropoietic porphyria. Physiol Res 55(Suppl 2):S85–S92

    PubMed  CAS  Google Scholar 

  176. Romeo G, Levin EY (1969) Uroporphyrinogen 3 cosynthetase in human congenital erythropoietic porphyria. Proc Natl Acad Sci USA 63:856–863

    PubMed  CAS  Google Scholar 

  177. Mendez M, Sorkin L, Rossetti MV, Astrin KH, del CBAM, Parera VE, Aizencang G, Desnick RJ (1998) Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles. Am J Hum Genet 63:1363–1375

  178. Schmitt C, Gouya L, Malonova E, Lamoril J, Camadro JM, Flamme M, Rose C, Lyoumi S, Da Silva V, Boileau C et al (2005) Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria. Hum Mol Genet 14:3089–3098

    PubMed  CAS  Google Scholar 

  179. Roberts AG, Puy H, Dailey TA, Morgan RR, Whatley SD, Dailey HA, Martasek P, Nordmann Y, Deybach JC, Elder GH (1998) Molecular characterization of homozygous variegate porphyria. Hum Mol Genet 7:1921–1925

    PubMed  CAS  Google Scholar 

  180. Rufenacht UB, Gouya L, Schneider-Yin X, Puy H, Schafer BW, Aquaron R, Nordmann Y, Minder EI, Deybach JC (1998) Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria. Am J Hum Genet 62:1341–1352

    PubMed  CAS  Google Scholar 

  181. Higgs DR, Vickers MA, Wilkie AO, Pretorius IM, Jarman AP, Weatherall DJ (1989) A review of the molecular genetics of the human alpha-globin gene cluster. Blood 73:1081–1104

    PubMed  CAS  Google Scholar 

  182. Weiss I, Cash FE, Coleman MB, Pressley A, Adams JG, Sanguansermsri T, Liebhaber SA, Steinberg MH (1990) Molecular basis for alpha-thalassemia associated with the structural mutant hemoglobin Suan-Dok (alpha 2 109leu—arg). Blood 76:2630–2636

    PubMed  CAS  Google Scholar 

  183. Tassiopoulos S, Deftereos S, Konstantopoulos K, Farmakis D, Tsironi M, Kyriakidis M, Aessopos A (2005) Does heterozygous beta-thalassemia confer a protection against coronary artery disease? Ann NY Acad Sci 1054:467–470

    PubMed  Google Scholar 

  184. Blouin MJ, Beauchemin H, Wright A, De Paepe M, Sorette M, Bleau AM, Nakamoto B, Ou CN, Stamatoyannopoulos G, Trudel M (2000) Genetic correction of sickle cell disease: insights using transgenic mouse models. Nat Med 6:177–182

    PubMed  CAS  Google Scholar 

  185. Chae JJ, Komarow HD, Cheng J, Wood G, Raben N, Liu PP, Kastner DL (2003) Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell 11:591–604

    PubMed  CAS  Google Scholar 

  186. Tzall S, Ellenbogen A, Eng F, Hirschhorn R (1989) Identification and characterization of nine RFLPs at the adenosine deaminase (ADA) locus. Am J Hum Genet 44:864–875

    PubMed  CAS  Google Scholar 

  187. Hirschhorn R, Vawter GF, Kirkpatrick JA Jr, Rosen FS (1979) Adenosine deaminase deficiency: frequency and comparative pathology in autosomally recessive severe combined immunodeficiency. Clin Immunol Immunopathol 14:107–120

    PubMed  CAS  Google Scholar 

  188. Speckmann C, Pannicke U, Wiech E, Schwarz K, Fisch P, Friedrich W, Niehues T, Gilmour K, Buiting K, Schlesier M et al (2008) Clinical and immunologic consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency. Blood 112:4090–4097

    PubMed  CAS  Google Scholar 

  189. Santagata S, Gomez CA, Sobacchi C, Bozzi F, Abinun M, Pasic S, Cortes P, Vezzoni P, Villa A (2000) N-terminal RAG1 frameshift mutations in Omenn’s syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains. Proc Natl Acad Sci USA 97:14572–14577

    PubMed  CAS  Google Scholar 

  190. Tabori U, Mark Z, Amariglio N, Etzioni A, Golan H, Biloray B, Toren A, Rechavi G, Dalal I (2004) Detection of RAG mutations and prenatal diagnosis in families presenting with either T-B- severe combined immunodeficiency or Omenn’s syndrome. Clin Genet 65:322–326

    PubMed  CAS  Google Scholar 

  191. Notarangelo LD, Mella P, Jones A, de Saint Basile G, Savoldi G, Cranston T, Vihinen M, Schumacher RF (2001) Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum Mutat 18:255–263

    PubMed  CAS  Google Scholar 

  192. Saglio G, Storlazzi CT, Giugliano E, Surace C, Anelli L, Rege-Cambrin G, Zagaria A, Jimenez Velasco A, Heiniger A, Scaravaglio P et al (2002) A 76-kb duplicon maps close to the BCR gene on chromosome 22 and the ABL gene on chromosome 9: possible involvement in the genesis of the Philadelphia chromosome translocation. Proc Natl Acad Sci USA 99:9882–9887

    PubMed  CAS  Google Scholar 

  193. Rae J, Newburger PE, Dinauer MC, Noack D, Hopkins PJ, Kuruto R, Curnutte JT (1998) X-Linked chronic granulomatous disease: mutations in the CYBB gene encoding the gp91-phox component of respiratory-burst oxidase. Am J Hum Genet 62:1320–1331

    PubMed  CAS  Google Scholar 

  194. Li A, Prasad A, Mincemoyer R, Satorius C, Epstein N, Finkel T, Quyyumi AA (1999) Relationship of the C242T p22phox gene polymorphism to angiographic coronary artery disease and endothelial function. Am J Med Genet 86:57–61

    PubMed  CAS  Google Scholar 

  195. Roos D, de Boer M, Koker MY, Dekker J, Singh-Gupta V, Ahlin A, Palmblad J, Sanal O, Kurenko-Deptuch M, Jolles S et al (2006) Chronic granulomatous disease caused by mutations other than the common GT deletion in NCF1, the gene encoding the p47phox component of the phagocyte NADPH oxidase. Hum Mutat 27:1218–1229

    PubMed  CAS  Google Scholar 

  196. Nunoi H, Iwata M, Tatsuzawa S, Onoe Y, Shimizu S, Kanegasaki S, Matsuda I (1995) AG dinucleotide insertion in a patient with chronic granulomatous disease lacking cytosolic 67-kD protein. Blood 86:329–333

    PubMed  CAS  Google Scholar 

  197. Santacroce R, Acquila M, Belvini D, Castaldo G, Garagiola I, Giacomelli SH, Lombardi AM, Minuti B, Riccardi F, Salviato R et al (2008) Identification of 217 unreported mutations in the F8 gene in a group of 1, 410 unselected Italian patients with hemophilia A. J Hum Genet 53:275–284

    PubMed  CAS  Google Scholar 

  198. Ljung R, Petrini P, Tengborn L, Sjorin E (2001) Haemophilia B mutations in Sweden: a population-based study of mutational heterogeneity. Br J Haematol 113:81–86

    PubMed  CAS  Google Scholar 

  199. Rogatko A, Auerbach AD (1988) Segregation analysis with uncertain ascertainment: application to Fanconi anemia. Am J Hum Genet 42:889–897

    PubMed  CAS  Google Scholar 

  200. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV (1995) Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 333:1253–1258

    PubMed  CAS  Google Scholar 

  201. Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, Bedell MA, Edelhoff S, Disteche CM, Simoneaux DK et al (1993) CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 259:990–993

    PubMed  CAS  Google Scholar 

  202. Stolarski B, Pronicka E, Korniszewski L, Pollak A, Kostrzewa G, Rowinska E, Wlodarski P, Skorka A, Gremida M, Krajewski P et al (2006) Molecular background of polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence. Clin Genet 70:348–354

    PubMed  CAS  Google Scholar 

  203. Ahonen P (1985) Autoimmune polyendocrinopathy–candidosis–ectodermal dystrophy (APECED): autosomal recessive inheritance. Clin Genet 27:535–542

    PubMed  CAS  Article  Google Scholar 

  204. Robertson KD, Jones PA (1999) Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus. Oncogene 18:3810–3820

    PubMed  CAS  Google Scholar 

  205. Kannengiesser C, Dalle S, Leccia MT, Avril MF, Bonadona V, Chompret A, Lasset C, Leroux D, Thomas L, Lesueur F et al (2007) New founder germline mutations of CDKN2A in melanoma-prone families and multiple primary melanoma development in a patient receiving levodopa treatment. Genes Chromosomes Cancer 46:751–760

    PubMed  CAS  Google Scholar 

  206. Lynch HT, Fusaro RM, Johnson JA (1984) Xeroderma pigmentosum. Complementation group C and malignant melanoma. Arch Dermatol 120:175–179

    PubMed  CAS  Google Scholar 

  207. Cleaver JE, Thompson LH, Richardson AS, States JC (1999) A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Hum Mutat 14:9–22

    PubMed  CAS  Google Scholar 

  208. Nichols AF, Ong P, Linn S (1996) Mutations specific to the xeroderma pigmentosum group E Ddb- phenotype. J Biol Chem 271:24317–24320

    PubMed  CAS  Google Scholar 

  209. Defesche JC, Schuurman EJ, Klaaijsen LN, Khoo KL, Wiegman A, Stalenhoef AF (2008) Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing. Clin Genet 73:573–578

    PubMed  CAS  Google Scholar 

  210. Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M (2006) Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Hum Mutat 27:626–632

    PubMed  CAS  Google Scholar 

  211. Nyhan WL, Wong DF (1996) New approaches to understanding Lesch-Nyhan disease. N Engl J Med 334:1602–1604

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported European Union MEGATOOLS (LSHG-CT-2006-037226), the Ministerio de Ciencia e Inovación (MICINN) Grant BFU2007-30703-E and BFU2008-01344 to G.M., and the ETORTEK-2008 programme, at the Structural Biology Unit of CIC bioGUNE. M.J.M. holds a Juan de la Cierva contract from the Spanish MICINN.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jesús Prieto or Guillermo Montoya.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Marcaida, M.J., Muñoz, I.G., Blanco, F.J. et al. Homing endonucleases: from basics to therapeutic applications. Cell. Mol. Life Sci. 67, 727–748 (2010). https://doi.org/10.1007/s00018-009-0188-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-009-0188-y

Keywords

  • Homing endonucleases
  • Protein engineering
  • Monogenic diseases
  • Double-strand break
  • DNA repair
  • Gene therapy
  • Protein structure
  • Protein–DNA interaction