Cellular and Molecular Life Sciences

, Volume 67, Issue 21, pp 3573–3587 | Cite as

Functions of disordered regions in mammalian early base excision repair proteins

  • Muralidhar L. Hegde
  • Tapas K. Hazra
  • Sankar MitraEmail author
Multi-Author Review


Reactive oxygen species, generated endogenously and induced as a toxic response, produce several dozen oxidized or modified bases and/or single-strand breaks in mammalian and other genomes. These lesions are predominantly repaired via the conserved base excision repair (BER) pathway. BER is initiated with excision of oxidized or modified bases by DNA glycosylases leading to formation of abasic (AP) site or strand break at the lesion site. Structural analysis by experimental and modeling approaches shows the presence of a disordered segment commonly localized at the N- or C-terminus as a characteristic signature of mammalian DNA glycosylases which is absent in their bacterial prototypes. Recent studies on unstructured regions in DNA metabolizing proteins have indicated their essential role in interaction with other proteins and target DNA recognition. In this review, we have discussed the unique presence of disordered segments in human DNA glycosylases, and AP endonuclease involved in the processing of glycosylase products, and their critical role in regulating repair functions. These disordered segments also include sites for posttranslational modifications and nuclear localization signal. The teleological basis for their structural flexibility is discussed.


Base excision repair DNA glycosylases End processing proteins Disordered terminal segments Single strand breaks Reactive oxygen species Repair complex Protein–protein and protein–DNA interactions 



Base excision repair


Single-strand break repair




AP endonuclease


Reactive oxygen species


Reactive nitrogen species


Single-strand break


Prediction of naturally disordered regions in proteins



The research in the authors’ laboratory is supported by USPHS grants, R01 CA81063, R01 CA53791, P01 CA92586 and P30 ES06676 (S.M.) and R01 CA 102271, R21 ES017353 (T.K.H). Because of the limited focus of the article on protein disorder in early BER proteins, many appropriate references could not be included, for which the authors apologize. We thank Mitra lab members for various stimulating discussions during preparation of this review.


  1. 1.
    Hegde ML, Hazra TK, Mitra S (2008) Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells. Cell Res 18:27–47PubMedCrossRefGoogle Scholar
  2. 2.
    Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90:7915–7922PubMedCrossRefGoogle Scholar
  3. 3.
    Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362:709–715PubMedCrossRefGoogle Scholar
  4. 4.
    Mitra S, Hazra TK, Roy R, Ikeda S, Biswas T, Lock J, Boldogh I, Izumi T (1997) Complexities of DNA base excision repair in mammalian cells. Mol Cells 7:305–312PubMedGoogle Scholar
  5. 5.
    Breen AP, Murphy JA (1995) Reactions of oxyl radicals with DNA. Free Radic Biol Med 18:1033–1077PubMedCrossRefGoogle Scholar
  6. 6.
    Demple B, DeMott MS (2002) Dynamics and diversions in base excision DNA repair of oxidized abasic lesions. Oncogene 21:8926–8934PubMedCrossRefGoogle Scholar
  7. 7.
    Wiederhold L, Leppard JB, Kedar P, Karimi-Busheri F, Rasouli-Nia A, Weinfeld M, Tomkinson AE, Izumi T, Prasad R, Wilson SH, Mitra S, Hazra TK (2004) Ap endonuclease-independent DNA base excision repair in human cells. Mol Cell 15:209–220PubMedCrossRefGoogle Scholar
  8. 8.
    Dou H, Mitra S, Hazra TK (2003) Repair of oxidized bases in DNA bubble structures by human DNA glycosylases neil1 and neil2. J Biol Chem 278:49679–49684PubMedCrossRefGoogle Scholar
  9. 9.
    Kavli B, Sundheim O, Akbari M, Otterlei M, Nilsen H, Skorpen F, Aas PA, Hagen L, Krokan HE, Slupphaug G (2002) Hung2 is the major repair enzyme for removal of uracil from u:A matches, u:G mismatches, and u in single-stranded DNA, with hsmug1 as a broad specificity backup. J Biol Chem 277:39926–39936PubMedCrossRefGoogle Scholar
  10. 10.
    Hegde ML, Theriot CA, Das A, Hegde PM, Guo Z, Gary RK, Hazra TK, Shen B, Mitra S (2008) Physical and functional interaction between human oxidized base-specific DNA glycosylase neil1 and flap endonuclease 1. J Biol Chem 283:27028–27037PubMedCrossRefGoogle Scholar
  11. 11.
    Dou H, Theriot CA, Das A, Hegde ML, Matsumoto Y, Boldogh I, Hazra TK, Bhakat KK, Mitra S (2008) Interaction of the human DNA glycosylase neil1 with proliferating cell nuclear antigen. The potential for replication-associated repair of oxidized bases in mammalian genomes. J Biol Chem 283:3130–3140PubMedCrossRefGoogle Scholar
  12. 12.
    Das A, Boldogh I, Lee JW, Harrigan JA, Hegde ML, Piotrowski J, de Souza Pinto N, Ramos W, Greenberg MM, Hazra TK, Mitra S, Bohr VA (2007) The human werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase neil1. J Biol Chem 282:26591–26602PubMedCrossRefGoogle Scholar
  13. 13.
    Theriot CA, Hegde ML, Hazra TK, Mitra S (2010) Rpa physically interacts with the human DNA glycosylase neil1 to regulate excision of oxidative DNA base damage in primer-template structures. DNA Repair (Amst) 9:643–652CrossRefGoogle Scholar
  14. 14.
    Lindahl T (1974) An n-glycosidase from Escherichia coli that releases free uracil from DNA containing deaminated cytosine residues. Proc Natl Acad Sci USA 71:3649–3653PubMedCrossRefGoogle Scholar
  15. 15.
    Friedberg EC, Aguilera A, Gellert M, Hanawalt PC, Hays JB, Lehmann AR, Lindahl T, Lowndes N, Sarasin A, Wood RD (2006) DNA repair: from molecular mechanism to human disease. DNA Repair (Amst) 5:986–996CrossRefGoogle Scholar
  16. 16.
    Krokan HE, Drablos F, Slupphaug G (2002) Uracil in DNA—occurrence, consequences and repair. Oncogene 21:8935–8948PubMedCrossRefGoogle Scholar
  17. 17.
    Hardeland U, Bentele M, Jiricny J, Schar P (2003) The versatile thymine DNA-glycosylase: a comparative characterization of the human, drosophila and fission yeast orthologs. Nucleic Acids Res 31:2261–2271PubMedCrossRefGoogle Scholar
  18. 18.
    Mitra S (2007) Mgmt: a personal perspective. DNA Repair (Amst) 6:1064–1070CrossRefGoogle Scholar
  19. 19.
    Demple B, Sedgwick B, Robins P, Totty N, Waterfield MD, Lindahl T (1985) Active site and complete sequence of the suicidal methyltransferase that counters alkylation mutagenesis. Proc Natl Acad Sci USA 82:2688–2692PubMedCrossRefGoogle Scholar
  20. 20.
    Tano K, Shiota S, Collier J, Foote RS, Mitra S (1990) Isolation and structural characterization of a cdna clone encoding the human DNA repair protein for O6-alkylguanine. Proc Natl Acad Sci USA 87:686–690PubMedCrossRefGoogle Scholar
  21. 21.
    Sedgwick B, Bates PA, Paik J, Jacobs SC, Lindahl T (2007) Repair of alkylated DNA: recent advances. DNA Repair (Amst) 6:429–442CrossRefGoogle Scholar
  22. 22.
    Mitra S, Kaina B (1993) Regulation of repair of alkylation damage in mammalian genomes. Prog Nucleic Acid Res Mol Biol 44:109–142PubMedCrossRefGoogle Scholar
  23. 23.
    Slupska MM, Luther WM, Chiang JH, Yang H, Miller JH (1999) Functional expression of hMYH, a human homolog of the Escherichia coli MutY protein. J Bacteriol 181:6210–6213PubMedGoogle Scholar
  24. 24.
    Nghiem Y, Cabrera M, Cupples CG, Miller JH (1988) The muty gene: a mutator locus in Escherichia coli that generates g.C…t.A transversions. Proc Natl Acad Sci USA 85:2709–2713PubMedCrossRefGoogle Scholar
  25. 25.
    Hazra TK, Izumi T, Kow YW, Mitra S (2003) The discovery of a new family of mammalian enzymes for repair of oxidatively damaged DNA, and its physiological implications. Carcinogenesis 24:155–157PubMedCrossRefGoogle Scholar
  26. 26.
    McCullough AK, Dodson ML, Lloyd RS (1999) Initiation of base excision repair: glycosylase mechanisms and structures. Annu Rev Biochem 68:255–285PubMedCrossRefGoogle Scholar
  27. 27.
    Hazra TK, Izumi T, Boldogh I, Imhoff B, Kow YW, Jaruga P, Dizdaroglu M, Mitra S (2002) Identification and characterization of a human DNA glycosylase for repair of modified bases in oxidatively damaged DNA. Proc Natl Acad Sci USA 99:3523–3528PubMedCrossRefGoogle Scholar
  28. 28.
    Hazra TK, Kow YW, Hatahet Z, Imhoff B, Boldogh I, Mokkapati SK, Mitra S, Izumi T (2002) Identification and characterization of a novel human DNA glycosylase for repair of cytosine-derived lesions. J Biol Chem 277:30417–30420PubMedCrossRefGoogle Scholar
  29. 29.
    Bandaru V, Sunkara S, Wallace SS, Bond JP (2002) A novel human DNA glycosylase that removes oxidative DNA damage and is homologous to Escherichia coli endonuclease viii. DNA Repair (Amst) 1:517–529CrossRefGoogle Scholar
  30. 30.
    Takao M, Kanno S, Shiromoto T, Hasegawa R, Ide H, Ikeda S, Sarker AH, Seki S, Xing JZ, Le XC, Weinfeld M, Kobayashi K, Miyazaki J, Muijtjens M, Hoeijmakers JH, van der Horst G, Yasui A (2002) Novel nuclear and mitochondrial glycosylases revealed by disruption of the mouse Nth1 gene encoding an endonuclease iii homolog for repair of thymine glycols. EMBO J 21:3486–3493PubMedCrossRefGoogle Scholar
  31. 31.
    Liu M, Bandaru V, Bond JP, Jaruga P, Zhao X, Christov PP, Burrows CJ, Rizzo CJ, Dizdaroglu M, Wallace SS (2010) The mouse ortholog of neil3 is a functional DNA glycosylase in vitro and in vivo. Proc Natl Acad Sci USA 107:4925–4930PubMedCrossRefGoogle Scholar
  32. 32.
    Zharkov DO, Shoham G, Grollman AP (2003) Structural characterization of the fpg family of DNA glycosylases. DNA Repair (Amst) 2:839–862CrossRefGoogle Scholar
  33. 33.
    Caldecott KW (2008) Single-strand break repair and genetic disease. Nat Rev Genet 9:619–631PubMedGoogle Scholar
  34. 34.
    Frosina G, Fortini P, Rossi O, Carrozzino F, Raspaglio G, Cox LS, Lane DP, Abbondandolo A, Dogliotti E (1996) Two pathways for base excision repair in mammalian cells. J Biol Chem 271:9573–9578PubMedCrossRefGoogle Scholar
  35. 35.
    Sobol RW, Prasad R, Evenski A, Baker A, Yang XP, Horton JK, Wilson SH (2000) The lyase activity of the DNA repair protein beta-polymerase protects from DNA-damage-induced cytotoxicity. Nature 405:807–810PubMedCrossRefGoogle Scholar
  36. 36.
    Ahel I, Rass U, El-Khamisy SF, Katyal S, Clements PM, McKinnon PJ, Caldecott KW, West SC (2006) The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates. Nature 443:713–716PubMedCrossRefGoogle Scholar
  37. 37.
    Rass U, Ahel I, West SC (2007) Actions of aprataxin in multiple DNA repair pathways. J Biol Chem 282:9469–9474PubMedCrossRefGoogle Scholar
  38. 38.
    Caldecott KW (2007) Mammalian single-strand break repair: mechanisms and links with chromatin. DNA Repair (Amst) 6:443–453CrossRefGoogle Scholar
  39. 39.
    Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW (2001) Xrcc1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell 104:107–117PubMedCrossRefGoogle Scholar
  40. 40.
    Parsons JL, Dianova II, Dianov GL (2004) Ape1 is the major 3′-phosphoglycolate activity in human cell extracts. Nucleic Acids Res 32:3531–3536PubMedCrossRefGoogle Scholar
  41. 41.
    Pouliot JJ, Robertson CA, Nash HA (2001) Pathways for repair of topoisomerase i covalent complexes in Saccharomyces cerevisiae. Genes Cells 6:677–687PubMedCrossRefGoogle Scholar
  42. 42.
    El-Khamisy SF, Saifi GM, Weinfeld M, Johansson F, Helleday T, Lupski JR, Caldecott KW (2005) Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature 434:108–113PubMedCrossRefGoogle Scholar
  43. 43.
    Yang SW, Burgin AB Jr, Huizenga BN, Robertson CA, Yao KC, Nash HA (1996) A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases. Proc Natl Acad Sci USA 93:11534–11539PubMedCrossRefGoogle Scholar
  44. 44.
    Pouliot JJ, Yao KC, Robertson CA, Nash HA (1999) Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase i complexes. Science 286:552–555PubMedCrossRefGoogle Scholar
  45. 45.
    Mazur DJ, Perrino FW (2001) Structure and expression of the trex1 and trex2 3′ → 5′ exonuclease genes. J Biol Chem 276:14718–14727PubMedCrossRefGoogle Scholar
  46. 46.
    Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, van Bokhoven H, Brunner HG, Hamel BC, Corry PC, Cowan FM, Frints SG, Klepper J, Livingston JH, Lynch SA, Massey RF, Meritet JF, Michaud JL, Ponsot G, Voit T, Lebon P, Bonthron DT, Jackson AP, Barnes DE, Lindahl T (2006) Mutations in the gene encoding the 3′–5′ DNA exonuclease trex1 cause aicardi-goutieres syndrome at the ags1 locus. Nat Genet 38:917–920PubMedCrossRefGoogle Scholar
  47. 47.
    Das A, Wiederhold L, Leppard JB, Kedar P, Prasad R, Wang H, Boldogh I, Karimi-Busheri F, Weinfeld M, Tomkinson AE, Wilson SH, Mitra S, Hazra TK (2006) Neil2-initiated, ape-independent repair of oxidized bases in DNA: evidence for a repair complex in human cells. DNA Repair (Amst) 5:1439–1448CrossRefGoogle Scholar
  48. 48.
    Vidal AE, Boiteux S, Hickson ID, Radicella JP (2001) Xrcc1 coordinates the initial and late stages of DNA abasic site repair through protein-protein interactions. EMBO J 20:6530–6539PubMedCrossRefGoogle Scholar
  49. 49.
    Lan L, Nakajima S, Oohata Y, Takao M, Okano S, Masutani M, Wilson SH, Yasui A (2004) In situ analysis of repair processes for oxidative DNA damage in mammalian cells. Proc Natl Acad Sci USA 101:13738–13743PubMedCrossRefGoogle Scholar
  50. 50.
    Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(adp-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7:517–528PubMedCrossRefGoogle Scholar
  51. 51.
    Kubota Y, Nash RA, Klungland A, Schar P, Barnes DE, Lindahl T (1996) Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the xrcc1 protein. EMBO J 15:6662–6670PubMedGoogle Scholar
  52. 52.
    Matsumoto Y (2001) Molecular mechanism of pcna-dependent base excision repair. Prog Nucleic Acid Res Mol Biol 68:129–138PubMedCrossRefGoogle Scholar
  53. 53.
    Klungland A, Lindahl T (1997) Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for dnase iv (fen1). EMBO J 16:3341–3348PubMedCrossRefGoogle Scholar
  54. 54.
    Maga G, Villani G, Tillement V, Stucki M, Locatelli GA, Frouin I, Spadari S, Hubscher U (2001) Okazaki fragment processing: modulation of the strand displacement activity of DNA polymerase delta by the concerted action of replication protein a, proliferating cell nuclear antigen, and flap endonuclease-1. Proc Natl Acad Sci USA 98:14298–14303PubMedCrossRefGoogle Scholar
  55. 55.
    Singh P, Zheng L, Chavez V, Qiu J, Shen B (2007) Concerted action of exonuclease and gap-dependent endonuclease activities of fen-1 contributes to the resolution of triplet repeat sequences (ctg)n- and (gaa)n-derived secondary structures formed during maturation of okazaki fragments. J Biol Chem 282:3465–3477PubMedCrossRefGoogle Scholar
  56. 56.
    Garg P, Stith CM, Sabouri N, Johansson E, Burgers PM (2004) Idling by DNA polymerase delta maintains a ligatable nick during lagging-strand DNA replication. Genes Dev 18:2764–2773PubMedCrossRefGoogle Scholar
  57. 57.
    Levin DS, McKenna AE, Motycka TA, Matsumoto Y, Tomkinson AE (2000) Interaction between pcna and DNA ligase i is critical for joining of okazaki fragments and long-patch base-excision repair. Curr Biol 10:919–922PubMedCrossRefGoogle Scholar
  58. 58.
    Prasad R, Dianov GL, Bohr VA, Wilson SH (2000) Fen1 stimulation of DNA polymerase beta mediates an excision step in mammalian long patch base excision repair. J Biol Chem 275:4460–4466PubMedCrossRefGoogle Scholar
  59. 59.
    Liu Y, Kao HI, Bambara RA (2004) Flap endonuclease 1: a central component of DNA metabolism. Annu Rev Biochem 73:589–615PubMedCrossRefGoogle Scholar
  60. 60.
    Piersen CE, Prasad R, Wilson SH, Lloyd RS (1996) Evidence for an imino intermediate in the DNA polymerase beta deoxyribose phosphate excision reaction. J Biol Chem 271:17811–17815PubMedCrossRefGoogle Scholar
  61. 61.
    Matsumoto Y, Kim K (1995) Excision of deoxyribose phosphate residues by DNA polymerase beta during DNA repair. Science 269:699–702PubMedCrossRefGoogle Scholar
  62. 62.
    Otterlei M, Warbrick E, Nagelhus TA, Haug T, Slupphaug G, Akbari M, Aas PA, Steinsbekk K, Bakke O, Krokan HE (1999) Post-replicative base excision repair in replication foci. EMBO J 18:3834–3844PubMedCrossRefGoogle Scholar
  63. 63.
    Hazra TK, Das A, Das S, Choudhury S, Kow YW, Roy R (2007) Oxidative DNA damage repair in mammalian cells: a new perspective. DNA Repair (Amst) 6:470–480CrossRefGoogle Scholar
  64. 64.
    Nagelhus TA, Haug T, Singh KK, Keshav KF, Skorpen F, Otterlei M, Bharati S, Lindmo T, Benichou S, Benarous R, Krokan HE (1997) A sequence in the N-terminal region of human uracil-DNA glycosylase with homology to xpa interacts with the C-terminal part of the 34-kDa subunit of replication protein a. J Biol Chem 272:6561–6566PubMedCrossRefGoogle Scholar
  65. 65.
    Parker A, Gu Y, Mahoney W, Lee SH, Singh KK, Lu AL (2001) Human homolog of the muty repair protein (hmyh) physically interacts with proteins involved in long patch DNA base excision repair. J Biol Chem 276:5547–5555PubMedCrossRefGoogle Scholar
  66. 66.
    Hagen L, Kavli B, Sousa MM, Torseth K, Liabakk NB, Sundheim O, Pena-Diaz J, Otterlei M, Horning O, Jensen ON, Krokan HE, Slupphaug G (2008) Cell cycle-specific ung2 phosphorylations regulate protein turnover, activity and association with rpa. EMBO J 27:51–61PubMedCrossRefGoogle Scholar
  67. 67.
    Guan X, Bai H, Shi G, Theriot CA, Hazra TK, Mitra S, Lu AL (2007) The human checkpoint sensor rad9-rad1-hus1 interacts with and stimulates neil1 glycosylase. Nucleic Acids Res 35:2463–2472PubMedCrossRefGoogle Scholar
  68. 68.
    Das S, Chattopadhyay R, Bhakat KK, Boldogh I, Kohno K, Prasad R, Wilson SH, Hazra TK (2007) Stimulation of neil2-mediated oxidized base excision repair via yb-1 interaction during oxidative stress. J Biol Chem 282:28474–28484PubMedCrossRefGoogle Scholar
  69. 69.
    Marenstein DR, Ocampo MT, Chan MK, Altamirano A, Basu AK, Boorstein RJ, Cunningham RP, Teebor GW (2001) Stimulation of human endonuclease iii by y box-binding protein 1 (DNA-binding protein b). Interaction between a base excision repair enzyme and a transcription factor. J Biol Chem 276:21242–21249PubMedCrossRefGoogle Scholar
  70. 70.
    Wilson SH, Kunkel TA (2000) Passing the baton in base excision repair. Nat Struct Biol 7:176–178PubMedCrossRefGoogle Scholar
  71. 71.
    Parikh SS, Mol CD, Hosfield DJ, Tainer JA (1999) Envisioning the molecular choreography of DNA base excision repair. Curr Opin Struct Biol 9:37–47PubMedCrossRefGoogle Scholar
  72. 72.
    Izumi T, Mitra S (1998) Deletion analysis of human ap-endonuclease: minimum sequence required for the endonuclease activity. Carcinogenesis 19:525–527PubMedCrossRefGoogle Scholar
  73. 73.
    Izumi T, Wiederhold LR, Roy G, Roy R, Jaiswal A, Bhakat KK, Mitra S, Hazra TK (2003) Mammalian DNA base excision repair proteins: their interactions and role in repair of oxidative DNA damage. Toxicology 193:43–65PubMedCrossRefGoogle Scholar
  74. 74.
    Bhakat KK, Izumi T, Yang SH, Hazra TK, Mitra S (2003) Role of acetylated human ap-endonuclease (ape1/ref-1) in regulation of the parathyroid hormone gene. EMBO J 22:6299–6309PubMedCrossRefGoogle Scholar
  75. 75.
    Fuxreiter M, Tompa P, Simon I, Uversky VN, Hansen JC, Asturias FJ (2008) Malleable machines take shape in eukaryotic transcriptional regulation. Nat Chem Biol 4:728–737PubMedCrossRefGoogle Scholar
  76. 76.
    Tompa P, Fuxreiter M (2008) Fuzzy complexes: polymorphism and structural disorder in protein–protein interactions. Trends Biochem Sci 33:2–8PubMedCrossRefGoogle Scholar
  77. 77.
    Doublie S, Bandaru V, Bond JP, Wallace SS (2004) The crystal structure of human endonuclease viii-like 1 (neil1) reveals a zincless finger motif required for glycosylase activity. Proc Natl Acad Sci USA 101:10284–10289PubMedCrossRefGoogle Scholar
  78. 78.
    Romero P, Obradovic Z, Li X, Garner EC, Brown CJ, Dunker AK (2001) Sequence complexity of disordered protein. Proteins 42:38–48PubMedCrossRefGoogle Scholar
  79. 79.
    Li X, Romero P, Rani M, Dunker AK, Obradovic Z (1999) Predicting protein disorder for N-, C-, and internal regions. Genome Inform Ser Workshop Genome Inform 10:30–40PubMedGoogle Scholar
  80. 80.
    Obradovic Z, Peng K, Vucetic S, Radivojac P, Dunker AK (2005) Exploiting heterogeneous sequence properties improves prediction of protein disorder. Proteins 61(Suppl 7):176–182PubMedCrossRefGoogle Scholar
  81. 81.
    Ishida T, Kinoshita K (2007) Prdos: prediction of disordered protein regions from amino acid sequence. Nucleic Acids Res 35:W460–W464PubMedCrossRefGoogle Scholar
  82. 82.
    Yang ZR, Thomson R, McNeil P, Esnouf RM (2005) Ronn: the bio-basis function neural network technique applied to the detection of natively disordered regions in proteins. Bioinformatics 21:3369–3376PubMedCrossRefGoogle Scholar
  83. 83.
    Prilusky J, Felder CE, Zeev-Ben-Mordehai T, Rydberg EH, Man O, Beckmann JS, Silman I, Sussman JL (2005) Foldindex: a simple tool to predict whether a given protein sequence is intrinsically unfolded. Bioinformatics 21:3435–3438PubMedCrossRefGoogle Scholar
  84. 84.
    Linding R, Russell RB, Neduva V, Gibson TJ (2003) Globplot: exploring protein sequences for globularity and disorder. Nucleic Acids Res 31:3701–3708PubMedCrossRefGoogle Scholar
  85. 85.
    Dosztanyi Z, Csizmok V, Tompa P, Simon I (2005) The pairwise energy content estimated from amino acid composition discriminates between folded and intrinsically unstructured proteins. J Mol Biol 347:827–839PubMedCrossRefGoogle Scholar
  86. 86.
    Dosztanyi Z, Csizmok V, Tompa P, Simon I (2005) Iupred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics 21:3433–3434PubMedCrossRefGoogle Scholar
  87. 87.
    Galzitskaya OV, Garbuzynskiy SO, Lobanov MY (2006) Foldunfold: web server for the prediction of disordered regions in protein chain. Bioinformatics 22:2948–2949PubMedCrossRefGoogle Scholar
  88. 88.
    Peng K, Radivojac P, Vucetic S, Dunker AK, Obradovic Z (2006) Length-dependent prediction of protein intrinsic disorder. BMC Bioinformatics 7:208PubMedCrossRefGoogle Scholar
  89. 89.
    Peng K, Vucetic S, Radivojac P, Brown CJ, Dunker AK, Obradovic Z (2005) Optimizing long intrinsic disorder predictors with protein evolutionary information. J Bioinform Comput Biol 3:35–60PubMedCrossRefGoogle Scholar
  90. 90.
    Romero Obradovic, Dunker K (1997) Sequence data analysis for long disordered regions prediction in the calcineurin family. Genome Inform Ser Workshop Genome Inform 8:110–124PubMedGoogle Scholar
  91. 91.
    Dyson HJ, Wright PE (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6:197–208PubMedCrossRefGoogle Scholar
  92. 92.
    Vucetic S, Brown CJ, Dunker AK, Obradovic Z (2003) Flavors of protein disorder. Proteins 52:573–584PubMedCrossRefGoogle Scholar
  93. 93.
    Mitchell PJ, Tjian R (1989) Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science 245:371–378PubMedCrossRefGoogle Scholar
  94. 94.
    O’Hare P, Williams G (1992) Structural studies of the acidic transactivation domain of the vmw65 protein of herpes simplex virus using 1 h nmr. Biochemistry 31:4150–4156PubMedCrossRefGoogle Scholar
  95. 95.
    Golovanov AP, Chuang TH, DerMardirossian C, Barsukov I, Hawkins D, Badii R, Bokoch GM, Lian LY, Roberts GC (2001) Structure-activity relationships in flexible protein domains: regulation of rho gtpases by rhogdi and d4 gdi. J Mol Biol 305:121–135PubMedCrossRefGoogle Scholar
  96. 96.
    Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey RW, Griswold MD, Chiu W, Garner EC, Obradovic Z (2001) Intrinsically disordered protein. J Mol Graph Model 19:26–59PubMedCrossRefGoogle Scholar
  97. 97.
    Uversky VN (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11:739–756PubMedCrossRefGoogle Scholar
  98. 98.
    Iakoucheva LM, Kimzey AL, Masselon CD, Bruce JE, Garner EC, Brown CJ, Dunker AK, Smith RD, Ackerman EJ (2001) Identification of intrinsic order and disorder in the DNA repair protein xpa. Protein Sci 10:560–571PubMedCrossRefGoogle Scholar
  99. 99.
    Radivojac P, Iakoucheva LM, Oldfield CJ, Obradovic Z, Uversky VN, Dunker AK (2007) Intrinsic disorder and functional proteomics. Biophys J 92:1439–1456PubMedCrossRefGoogle Scholar
  100. 100.
    Toth-Petroczy A, Simon I, Fuxreiter M, Levy Y (2009) Disordered tails of homeodomains facilitate DNA recognition by providing a trade-off between folding and specific binding. J Am Chem Soc 131:15084–15085PubMedCrossRefGoogle Scholar
  101. 101.
    Vuzman D, Azia A, Levy Y (2010) Searching DNA via a “Monkey bar” mechanism: the significance of disordered tails. J Mol Biol 396:674–684PubMedCrossRefGoogle Scholar
  102. 102.
    He B, Wang K, Liu Y, Xue B, Uversky VN, Dunker AK (2009) Predicting intrinsic disorder in proteins: an overview. Cell Res 19:929–949PubMedCrossRefGoogle Scholar
  103. 103.
    Thayer MM, Ahern H, Xing D, Cunningham RP, Tainer JA (1995) Novel DNA binding motifs in the DNA repair enzyme endonuclease iii crystal structure. EMBO J 14:4108–4120PubMedGoogle Scholar
  104. 104.
    Ikeda S, Biswas T, Roy R, Izumi T, Boldogh I, Kurosky A, Sarker AH, Seki S, Mitra S (1998) Purification and characterization of human nth1, a homolog of Escherichia coli endonuclease iii. Direct identification of lys-212 as the active nucleophilic residue. J Biol Chem 273:21585–21593PubMedCrossRefGoogle Scholar
  105. 105.
    Liu X, Roy R (2002) Truncation of amino-terminal tail stimulates activity of human endonuclease III (hnth1). J Mol Biol 321:265–276PubMedCrossRefGoogle Scholar
  106. 106.
    Stein A, Pache RA, Bernado P, Pons M, Aloy P (2009) Dynamic interactions of proteins in complex networks: a more structured view. FEBS J 276:5390–5405PubMedCrossRefGoogle Scholar
  107. 107.
    Mittag T, Kay LE, Forman-Kay JD (2010) Protein dynamics and conformational disorder in molecular recognition. J Mol Recognit 23:105–116PubMedGoogle Scholar
  108. 108.
    Krueger KE, Srivastava S (2006) Posttranslational protein modifications: current implications for cancer detection, prevention, and therapeutics. Mol Cell Proteomics 5:1799–1810PubMedCrossRefGoogle Scholar
  109. 109.
    Busso CS, Iwakuma T, Izumi T (2009) Ubiquitination of mammalian ap endonuclease (ape1) regulated by the p53-mdm2 signaling pathway. Oncogene 28:1616–1625PubMedCrossRefGoogle Scholar
  110. 110.
    Lee H, Mok KH, Muhandiram R, Park KH, Suk JE, Kim DH, Chang J, Sung YC, Choi KY, Han KH (2000) Local structural elements in the mostly unstructured transcriptional activation domain of human p53. J Biol Chem 275:29426–29432PubMedCrossRefGoogle Scholar
  111. 111.
    Seet BT, Dikic I, Zhou MM, Pawson T (2006) Reading protein modifications with interaction domains. Nat Rev Mol Cell Biol 7:473–483PubMedCrossRefGoogle Scholar
  112. 112.
    Bhakat KK, Hazra TK, Mitra S (2004) Acetylation of the human DNA glycosylase neil2 and inhibition of its activity. Nucleic Acids Res 32:3033–3039PubMedCrossRefGoogle Scholar
  113. 113.
    Tini M, Benecke A, Um SJ, Torchia J, Evans RM, Chambon P (2002) Association of cbp/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription. Mol Cell 9:265–277PubMedCrossRefGoogle Scholar
  114. 114.
    Bhakat KK, Mokkapati SK, Boldogh I, Hazra TK, Mitra S (2006) Acetylation of human 8-oxoguanine-DNA glycosylase by p300 and its role in 8-oxoguanine repair in vivo. Mol Cell Biol 26:1654–1665PubMedCrossRefGoogle Scholar
  115. 115.
    Dingwall C, Laskey RA (1991) Nuclear targeting sequences—a consensus? Trends Biochem Sci 16:478–481PubMedCrossRefGoogle Scholar
  116. 116.
    Lee BJ, Cansizoglu AE, Suel KE, Louis TH, Zhang Z, Chook YM (2006) Rules for nuclear localization sequence recognition by karyopherin beta 2. Cell 126:543–558PubMedCrossRefGoogle Scholar
  117. 117.
    Jackson EB, Theriot CA, Chattopadhyay R, Mitra S, Izumi T (2005) Analysis of nuclear transport signals in the human apurinic/apyrimidinic endonuclease (ape1/ref1). Nucleic Acids Res 33:3303–3312PubMedCrossRefGoogle Scholar
  118. 118.
    Sarker AH, Ikeda S, Nakano H, Terato H, Ide H, Imai K, Akiyama K, Tsutsui K, Bo Z, Kubo K, Yamamoto K, Yasui A, Yoshida MC, Seki S (1998) Cloning and characterization of a mouse homologue (mnthl1) of Escherichia coli endonuclease iii. J Mol Biol 282:761–774PubMedCrossRefGoogle Scholar
  119. 119.
    Ikeda S, Kohmoto T, Tabata R, Seki Y (2002) Differential intracellular localization of the human and mouse endonuclease iii homologs and analysis of the sorting signals. DNA Repair (Amst) 1:847–854CrossRefGoogle Scholar
  120. 120.
    Otterlei M, Haug T, Nagelhus TA, Slupphaug G, Lindmo T, Krokan HE (1998) Nuclear and mitochondrial splice forms of human uracil–DNA glycosylase contain a complex nuclear localisation signal and a strong classical mitochondrial localisation signal, respectively. Nucleic Acids Res 26:4611–4617PubMedCrossRefGoogle Scholar
  121. 121.
    Berg OG, Winter RB, von Hippel PH (1981) Diffusion-driven mechanisms of protein translocation on nucleic acids. 1. Models and theory. Biochemistry 20:6929–6948PubMedCrossRefGoogle Scholar
  122. 122.
    Haynes C, Oldfield CJ, Ji F, Klitgord N, Cusick ME, Radivojac P, Uversky VN, Vidal M, Iakoucheva LM (2006) Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes. PLoS Comput Biol 2:e100PubMedCrossRefGoogle Scholar
  123. 123.
    Shimizu K, Toh H (2009) Interaction between intrinsically disordered proteins frequently occurs in a human protein–protein interaction network. J Mol Biol 392:1253–1265PubMedCrossRefGoogle Scholar
  124. 124.
    Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN (2005) Flexible nets. The roles of intrinsic disorder in protein interaction networks. Febs J 272:5129–5148PubMedCrossRefGoogle Scholar
  125. 125.
    Pontius BW (1993) Close encounters: why unstructured, polymeric domains can increase rates of specific macromolecular association. Trends Biochem Sci 18:181–186PubMedCrossRefGoogle Scholar
  126. 126.
    Shoemaker BA, Portman JJ, Wolynes PG (2000) Speeding molecular recognition by using the folding funnel: the fly-casting mechanism. Proc Natl Acad Sci USA 97:8868–8873PubMedCrossRefGoogle Scholar
  127. 127.
    Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP (1996) Crystal structure of the p27kip1 cyclin-dependent-kinase inhibitor bound to the cyclin a-cdk2 complex. Nature 382:325–331PubMedCrossRefGoogle Scholar
  128. 128.
    Kiss R, Bozoky Z, Kovacs D, Rona G, Friedrich P, Dvortsak P, Weisemann R, Tompa P, Perczel A (2008) Calcium-induced tripartite binding of intrinsically disordered calpastatin to its cognate enzyme, calpain. FEBS Lett 582:2149–2154PubMedCrossRefGoogle Scholar
  129. 129.
    Brown CJ, Takayama S, Campen AM, Vise P, Marshall TW, Oldfield CJ, Williams CJ, Dunker AK (2002) Evolutionary rate heterogeneity in proteins with long disordered regions. J Mol Evol 55:104–110PubMedCrossRefGoogle Scholar
  130. 130.
    Tokuriki N, Tawfik DS (2009) Protein dynamism and evolvability. Science 324:203–207PubMedCrossRefGoogle Scholar
  131. 131.
    Romero PR, Zaidi S, Fang YY, Uversky VN, Radivojac P, Oldfield CJ, Cortese MS, Sickmeier M, LeGall T, Obradovic Z, Dunker AK (2006) Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc Natl Acad Sci USA 103:8390–8395PubMedCrossRefGoogle Scholar
  132. 132.
    Gunasekaran K, Tsai CJ, Kumar S, Zanuy D, Nussinov R (2003) Extended disordered proteins: targeting function with less scaffold. Trends Biochem Sci 28:81–85PubMedCrossRefGoogle Scholar
  133. 133.
    Chen X, Zhong S, Zhu X, Dziegielewska B, Ellenberger T, Wilson GM, MacKerell AD Jr, Tomkinson AE (2008) Rational design of human DNA ligase inhibitors that target cellular DNA replication and repair. Cancer Res 68:3169–3177PubMedCrossRefGoogle Scholar
  134. 134.
    Drew Y, Plummer R (2009) Parp inhibitors in cancer therapy: two modes of attack on the cancer cell widening the clinical applications. Drug Resist Updat 12:153–156PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Muralidhar L. Hegde
    • 1
  • Tapas K. Hazra
    • 1
    • 2
  • Sankar Mitra
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular BiologyUniversity of Texas Medical BranchGalvestonUSA
  2. 2.Department of Internal MedicineUniversity of Texas Medical BranchGalvestonUSA

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