Role of lamin B1 in chromatin instability

Molecular and Cellular Biology

Volumn 35, Issue 5, 2015, Pages 884-898

  Butin Israeli, Veronika ^a   Adam, Stephen A ^a   Jain, Nikhil ^a   Otte, Gabriel L ^b   Neems, Daniel ^a   Wiesmüller, Lisa ^c   Berger, Shelly L ^b   Goldman, Robert D ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

^c UNIVERSITY OF ULM   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

BRCA1 PROTEIN; HISTONE H2AX; LAMIN B; LAMIN B1; MESSENGER RNA; MRE11 PROTEIN; NIBRIN; RAD50 PROTEIN; RAD51 PROTEIN; SHORT HAIRPIN RNA; SUMO 1 PROTEIN; UNCLASSIFIED DRUG; BRCA1 PROTEIN, HUMAN; CHROMATIN; RAD51 PROTEIN, HUMAN;

ARTICLE; CANCER CELL LINE; CELL CYCLE S PHASE; CELL PROLIFERATION; CHROMATIN; CHROMATIN ASSEMBLY AND DISASSEMBLY; CHROMOSOMAL INSTABILITY; DNA DAMAGE; DNA END JOINING REPAIR; DNA REPAIR; DNA REPLICATION; DOUBLE STRANDED DNA BREAK; DOWN REGULATION; GENE SILENCING; HUMAN; HUMAN CELL; OSTEOSARCOMA CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; SIGNAL TRANSDUCTION; STABLE EXPRESSION; SUMOYLATION; APOPTOSIS; CELL CYCLE; CHEMISTRY; GENE EXPRESSION REGULATION; METABOLISM; RNA INTERFERENCE; TUMOR CELL LINE;

APOPTOSIS; BRCA1 PROTEIN; CELL CYCLE; CELL LINE, TUMOR; CHROMATIN; DNA BREAKS, DOUBLE-STRANDED; DNA DAMAGE; DNA REPAIR; DNA REPLICATION; GENE EXPRESSION REGULATION; GENE EXPRESSION REGULATION, NEOPLASTIC; GENE SILENCING; HUMANS; LAMIN TYPE B; RAD51 RECOMBINASE; RNA INTERFERENCE; S PHASE;

EID: 84961288216     PISSN: 02707306     EISSN: 10985549     Source Type: Journal    
DOI: 10.1128/MCB.01145-14     Document Type: Article

References (79)

1. Dechat T, Adam SA, Taimen P, Shimi T, Goldman RD. 2010. Nuclear lamins. Cold Spring Harb Perspect Biol 2:a000547. http://dx.doi.org/10 .1101/cshperspect.a000547.
2. Stewart C, Burke B. 1987. Teratocarcinoma stem cells and early mouse embryos contain only a single major lamin polypeptide closely resembling lamin B Cell 51:383-392.
3. Dittmer TA, Misteli T. 2011. The lamin protein family. Genome Biol 12:222. http://dx.doi.org/10.1186/gb-2011-12-5-222.
4. Shimi T, Butin-Israeli V, Goldman RD. 2012. The functions of the nuclear envelope in mediating the molecular crosstalk between the nucleus and the cytoplasm. Curr Opin Cell Biol 24:71-78. http://dx.doi.org /10.1016/j.ceb.2011.11.007.
5. Singh M, Hunt CR, Pandita RK, Kumar R, Yang CR, Horikoshi N, Bachoo R, Serag S, Story MD, Shay JW, Powell SN, Gupta A, Jeffery J, Pandita S, Chen BP, Deckbar D, Lobrich M, Yang Q, Khanna KK, Worman HJ, Pandita TK. 2013. Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest. Mol Cell Biol 33:1210- 1222. http://dx.doi.org/10.1128/MCB.01676-12.
6. Liu Y, Rusinol A, Sinensky M, Wang Y, Zou Y. 2006. DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A. J Cell Sci 119:4644-4649. http://dx.doi.org/10.1242/jcs .03263.
7. Varela I, Cadinanos J, Pendas AM, Gutierrez-Fernandez A, Folgueras AR, Sanchez LM, Zhou Z, Rodriguez FJ, Stewart CL, Vega JA, Tryggvason K, Freije JM, Lopez-Otin C. 2005. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature 437:564-568. http://dx.doi.org/10.1038/nature04019.
8. Liu Y, Wang Y, Rusinol AE, Sinensky MS, Liu J, Shell SM, Zou Y. 2008. Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A. FASEB J 22:603-611. http: //dx.doi.org/10.1096/fj.07-8598com.
9. Padiath QS, Saigoh K, Schiffmann R, Asahara H, Yamada T, Koeppen A, Hogan K, Ptacek LJ, Fu YH. 2006. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet 38:1114-1123. http://dx .doi.org/10.1038/ng1872.
10. Brussino A, Vaula G, Cagnoli C, Panza E, Seri M, Di Gregorio E, Scappaticci S, Camanini S, Daniele D, Bradac GB, Pinessi L, Cavalieri S, Grosso E, Migone N, Brusco A. 2010. A family with autosomal dominant leukodystrophy linked to 5q23.2-q23.3 without lamin B1 mutations. Eur J Neurol 17:541-549. http://dx.doi.org/10.1111/j.1468-1331.2009 .02844.x.
11. Coffinier C, Chang SY, Nobumori C, Tu Y, Farber EA, Toth JI, Fong LG, Young SG. 2010. Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency. Proc Natl Acad Sci U S A 107:5076-5081. http://dx.doi.org/10.1073/pnas.0908790107.
12. Coffinier C, Jung HJ, Nobumori C, Chang S, Tu Y, Barnes RH, II, Yoshinaga Y, de Jong PJ, Vergnes L, Reue K, Fong LG, Young SG. 2011. Deficiencies in lamin B1 and lamin B2 cause neurodevelopmental defects and distinct nuclear shape abnormalities in neurons. Mol Biol Cell 22: 4683-4693. http://dx.doi.org/10.1091/mbc.E11-06-0504.
13. Kim Y, Sharov AA, McDole K, Cheng M, Hao H, Fan CM, Gaiano N, Ko MS, Zheng Y. 2011. Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells. Science 334:1706-1710. http://dx.doi.org/10.1126/science.1211222.
14. Yang SH, Chang SY, Yin L, Tu Y, Hu Y, Yoshinaga Y, de Jong PJ, Fong LG, Young SG. 2011. An absence of both lamin B1 and lamin B2 in keratinocytes has no effect on cell proliferation or the development of skin and hair. Hum Mol Genet 20:3537-3544. http://dx.doi.org/10.1093/hmg /ddr266.
15. Moss SF, Krivosheyev V, de Souza A, Chin K, Gaetz HP, Chaudhary N, Worman HJ, Holt PR. 1999. Decreased and aberrant nuclear lamin expression in gastrointestinal tract neoplasms. Gut 45:723-729. http://dx .doi.org/10.1136/gut.45.5.723.
16. Broers JL, Raymond Y, Rot MK, Kuijpers H, Wagenaar SS, Ramaekers FC. 1993. Nuclear A-type lamins are differentially expressed in human lung cancer subtypes. Am J Pathol 143:211-220.
17. Dreesen O, Chojnowski A, Ong PF, Zhao TY, Common JE, Lunny D, Lane EB, Lee SJ, Vardy LA, Stewart CL, Colman A. 2013. Lamin B1 fluctuations have differential effects on cellular proliferation and senescence. J Cell Biol 200:605-617. http://dx.doi.org/10.1083/jcb.201206121.
18. Shimi T, Butin-Israeli V, Adam SA, Hamanaka RB, Goldman AE, Lucas CA, Shumaker DK, Kosak ST, Chandel NS, Goldman RD. 2011. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev 25:2579-2593. http://dx.doi.org/10.1101/gad.179515.111.
19. Freund A, Laberge RM, Demaria M, Campisi J. 2012. Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell 23:2066-2075. http://dx .doi.org/10.1091/mbc.E11-10-0884.
20. Butin-Israeli V, Adam SA, Goldman RD. 2013. Regulation of nucleotide excision repair by nuclear lamin b1. PLoS One 8:e69169. http://dx.doi.org /10.1371/journal.pone.0069169.
21. Barascu A, Le Chalony C, Pennarun G, Genet D, Imam N, Lopez B, Bertrand P. 2012. Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation. EMBO J 31:1080-1094. http://dx.doi.org/10.1038/emboj.2011.492.
22. Laemmli UK. 1970. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680-685. http://dx.doi.org/10 .1038/227680a0.
23. Moir RD, Montag-Lowy M, Goldman RD. 1994. Dynamic properties of nuclear lamins: lamin B is associated with sites of DNA replication. J Cell Biol 125:1201-1212. http://dx.doi.org/10.1083/jcb.125.6.1201.
24. Yokochi T, Gilbert DM. 2007. Replication labeling with halogenated thymidine analogs. Curr Protoc Cell Biol Chapter 22:Unit 22.10. http://dx .doi.org/10.1002/0471143030.cb2210s35.
25. Akyüz N, Boehden GS, Susse S, Rimek A, Preuss U, Scheidtmann KH, Wiesmüller L. 2002. DNA substrate dependence of p53-mediated regulation of double-strand break repair. Mol Cell Biol 22:6306-6317. http: //dx.doi.org/10.1128/MCB.22.17.6306-6317.2002.
26. Keimling M, Volcic M, Csernok A, Wieland B, Dork T, Wiesmüller L. 2011. Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways. FASEB J 25:3849-3860. http://dx.doi.org/10.1096/fj.11-185546.
27. Keimling M, Deniz M, Varga D, Stahl A, Schrezenmeier H, Kreienberg R, Hoffmann I, Konig J, Wiesmüller L. 2012. The power of DNA doublestrand break (DSB) repair testing to predict breast cancer susceptibility. FASEB J 26:2094-2104. http://dx.doi.org/10.1096/fj.11-200790.
28. Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. 2006. Clonogenic assay of cells in vitro. Nat Protoc 1:2315-2319. http://dx.doi .org/10.1038/nprot.2006.339.
29. Munshi A, Hobbs M, Meyn RE. 2005. Clonogenic cell survival assay. Methods Mol Med 110:21-28. http://dx.doi.org/10.1385/1-59259-869 -2:021.
30. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G. 2000. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25:25-29. http://dx.doi.org/10.1038/75556.
31. Huang DW, Sherman BT, Lempicki RA. 2009. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44-57. http://dx.doi.org/10.1038/nprot.2008.211.
32. Ryba T, Battaglia D, Pope BD, Hiratani I, Gilbert DM. 2011. Genomescale analysis of replication timing: from bench to bioinformatics. Nat Protoc 6:870-895. http://dx.doi.org/10.1038/nprot.2011.328.
33. Spann TP, Moir RD, Goldman AE, Stick R, Goldman RD. 1997. Disruption of nuclear lamin organization alters the distribution of replication factors and inhibitsDNAsynthesis. J Cell Biol 136:1201-1212. http: //dx.doi.org/10.1083/jcb.136.6.1201.
34. Kanoh Y, Tamai K, Shirahige K. 2006. Different requirements for the association of ATR-ATRIP and 9-1-1 to the stalled replication forks. Gene 377:88-95. http://dx.doi.org/10.1016/j.gene.2006.03.019.
35. Van C, Yan S, Michael WM, Waga S, Cimprich KA. 2010. Continued primer synthesis at stalled replication forks contributes to checkpoint activation. J Cell Biol 189:233-246. http://dx.doi.org/10.1083/jcb .200909105.
36. MacDougall CA, Byun TS, Van C, Yee MC, Cimprich KA. 2007. The structural determinants of checkpoint activation. Genes Dev 21:898-903. http://dx.doi.org/10.1101/gad.1522607.
37. Alcasabas AA, Osborn AJ, Bachant J, Hu F, Werler PJ, Bousset K, Furuya K, Diffley JF, Carr AM, Elledge SJ. 2001. Mrc1 transduces signals ofDNAreplication stress to activate Rad53. Nat Cell Biol 3:958-965. http: //dx.doi.org/10.1038/ncb1101-958.
38. Branzei D, Foiani M. 2005. The DNA damage response during DNA replication. Curr Opin Cell Biol 17:568-575. http://dx.doi.org/10.1016/j .ceb.2005.09.003.
39. Branzei D, Foiani M. 2010. Maintaining genome stability at the replication fork. Nat Rev Mol Cell Biol 11:208-219. http://dx.doi.org/10.1038 /nrm2852.
40. Nam EA, Cortez D. 2011. ATR signalling: more than meeting at the fork. Biochem J 436:527-536. http://dx.doi.org/10.1042/BJ20102162.
41. Jones RM, Petermann E. 2012. Replication fork dynamics and the DNA damage response. Biochem J 443:13-26. http://dx.doi.org/10 .1042/BJ20112100.
42. FitzGerald JE, Grenon M, Lowndes NF. 2009. 53BP1: function and mechanisms of focal recruitment. Biochem Soc Trans 37:897-904. http: //dx.doi.org/10.1042/BST0370897.
43. Cleaver JE. 2011. γH2Ax: biomarker of damage or functional participant in DNA repair "all that glitters is not gold! " Photochem Photobiol 87: 1230-1239. http://dx.doi.org/10.1111/j.1751-1097.2011.00995.x.
44. Lukas J, Lukas C, Bartek J. 2011. More than just a focus: the chromatin response to DNA damage and its role in genome integrity maintenance. Nat Cell Biol 13:1161-1169. http://dx.doi.org/10.1038/ncb2344.
45. Pommier Y. 2006. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 6:789-802. http://dx.doi.org/10.1038/nrc1977.
46. Pommier Y. 2009. DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition. Chem Rev 109:2894-2902. http://dx.doi.org/10 .1021/cr900097c.
47. Lazo JS. 1999. Bleomycin. Cancer Chemother Biol Response Modif 18: 39-45.
48. Povirk LF. 1996. DNA damage and mutagenesis by radiomimetic DNAcleaving agents: bleomycin, neocarzinostatin and other enediynes. Mutat Res 355:71-89. http://dx.doi.org/10.1016/0027-5107(96)00023-1.
49. Williams GJ, Lees-Miller SP, Tainer JA. 2010. Mre11-Rad50-Nbs1 conformations and the control of sensing, signaling, and effector responses at DNA double-strand breaks. DNA Repair (Amst) 9:1299-1306. http://dx .doi.org/10.1016/j.dnarep.2010.10.001.
50. Burma S, Chen BP, Chen DJ. 2006. Role of non-homologous end joining (NHEJ) in maintaining genomic integrity. DNA Repair (Amst) 5:1042- 1048. http://dx.doi.org/10.1016/j.dnarep.2006.05.026.
51. Pardo B, Gomez-Gonzalez B, Aguilera A. 2009. DNA repair in mammalian cells: DNA double-strand break repair: how to fix a broken relationship. Cell Mol Life Sci 66:1039-1056. http://dx.doi.org/10.1007/s00018 -009-8740-3.
52. Papamichos-Chronakis M, Peterson CL. 2013. Chromatin and the genome integrity network. Nat Rev Genet 14:62-75. http://dx.doi.org/10 .1038/nri3604.
53. Guelen L, Pagie L, Brasset E, Meuleman W, Faza MB, Talhout W, Eussen BH, de Klein A, Wessels L, de Laat W, van Steensel B. 2008. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453:948-951. http://dx.doi.org/10 .1038/nature06947.
54. Shah PP, Donahue G, Otte GL, Capell BC, Nelson DM, Cao K, Aggarwala V, Cruickshanks HA, Rai TS, McBryan T, Gregory BD, Adams PD, Berger SL. 2013. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev 27: 1787-1799. http://dx.doi.org/10.1101/gad.223834.113.
55. Moir RD, Spann TP, Herrmann H, Goldman RD. 2000. Disruption of nuclear lamin organization blocks the elongation phase of DNA replication. J Cell Biol 149:1179-1192. http://dx.doi.org/10.1083/jcb.149.6.1179.
56. Camps J, Wangsa D, Falke M, Brown M, Case CM, Erdos MR, Ried T. 2014. Loss of lamin B1 results in prolongation of S phase and decondensation of chromosome territories. FASEB J 28:3423-3434. http://dx.doi .org/10.1096/fj.14-250456.
57. Tang CW, Maya-Mendoza A, Martin C, Zeng K, Chen S, Feret D, Wilson SA, Jackson DA. 2008. The integrity of a lamin-B1-dependent nucleoskeleton is a fundamental determinant of RNA synthesis in human cells. J Cell Sci 121:1014-1024. http://dx.doi.org/10.1242/jcs.020982.
58. Shumaker DK, Solimando L, Sengupta K, Shimi T, Adam SA, Grunwald A, Strelkov SV, Aebi U, Cardoso MC, Goldman RD. 2008. The highly conserved nuclear lamin Ig-fold binds to PCNA: its role in DNA replication. J Cell Biol 181:269-280. http://dx.doi.org/10.1083/jcb .200708155.
59. Moynahan ME, Jasin M. 2010. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol 11:196-207. http://dx.doi.org/10.1038/nrm2851.
60. Liu JS, Kuo SR, Melendy T. 2006. DNA damage-induced RPA focalization is independent of gamma-H2AX and RPA hyper-phosphorylation. J Cell Biochem 99:1452-1462. http://dx.doi.org/10.1002/jcb.21066.
61. Li X, Heyer WD. 2008. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 18:99-113. http://dx.doi.org/10.1038/cr .2008.1.
62. Shrivastav M, De Haro LP, Nickoloff JA. 2008. Regulation of DNA double-strand break repair pathway choice. Cell Res 18:134-147. http: //dx.doi.org/10.1038/cr.2007.111.
63. Allen C, Ashley AK, Hromas R, Nickoloff JA. 2011. More forks on the road to replication stress recovery. J Mol Cell Biol 3:4-12. http://dx.doi .org/10.1093/jmcb/mjq049.
64. Lamarche BJ, Orazio NI, Weitzman MD. 2010. The MRN complex in double-strand break repair and telomere maintenance. FEBS Lett 584: 3682-3695. http://dx.doi.org/10.1016/j.febslet.2010.07.029.
65. Kondratenko I, Paschenko O, Polyakov A, Bologov A. 2007. Nijmegen breakage syndrome. Adv Exp Med Biol 601:61-67. http://dx.doi.org/10 .1007/978-0-387-72005-0_6.
66. Arias-Lopez C, Lazaro-Trueba I, Kerr P, Lord CJ, Dexter T, Iravani M, Ashworth A, Silva A. 2006. p53 modulates homologous recombination by transcriptional regulation of the RAD51 gene. EMBO Rep 7:219-224. http://dx.doi.org/10.1038/sj.embor.7400587.
67. Lund E, Oldenburg AR, Delbarre E, Freberg CT, Duband-Goulet I, Eskeland R, Buendia B, Collas P. 2013. Lamin A/C-promoter interactions specify chromatin state-dependent transcription outcomes. Genome Res 23:1580-1589. http://dx.doi.org/10.1101/gr.159400.113.
68. Sadaie M, Salama R, Carroll T, Tomimatsu K, Chandra T, Young AR, Narita M, Perez-Mancera PA, Bennett DC, Chong H, Kimura H, Narita M. 2013. Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence. Genes Dev 27:1800-1808. http://dx.doi.org/10.1101/gad .217281.113.
69. Zullo JM, Demarco IA, Pique-Regi R, Gaffney DJ, Epstein CB, Spooner CJ, Luperchio TR, Bernstein BE, Pritchard JK, Reddy KL, Singh H. 2012. DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell 149:1474-1487. http://dx.doi.org /10.1016/j.cell.2012.04.035.
70. Muck JS, Kandasamy K, Englmann A, Gunther M, Zink D. 2012. Perinuclear positioning of the inactive human cystic fibrosis gene depends on CTCF, A-type lamins and an active histone deacetylase. J Cell Biochem 113:2607-2621. http://dx.doi.org/10.1002/jcb.24136.
71. Shimi T, Pfleghaar K, Kojima S, Pack CG, Solovei I, Goldman AE, Adam SA, Shumaker DK, Kinjo M, Cremer T, Goldman RD. 2008. The A- and B-type nuclear lamin networks: microdomains involved in chromatin organization and transcription. Genes Dev 22:3409-3421. http://dx .doi.org/10.1101/gad.1735208.
72. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. 2003. Recurrent de novo point mutations in lamin A cause Hutchinson- Gilford progeria syndrome. Nature 423:293-298. http://dx.doi.org/10 .1038/nature01629.
73. Muralikrishna B, Chaturvedi P, Sinha K, Parnaik VK. 2012. Lamin misexpression upregulates three distinct ubiquitin ligase systems that degrade ATR kinase in HeLa cells. Mol Cell Biochem 365:323-332. http://dx .doi.org/10.1007/s11010-012-1272-4.
74. Musich PR, Zou Y. 2009. Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A. Aging (Albany NY) 1:28-37.
75. Constantinescu D, Csoka AB, Navara CS, Schatten GP. 2010. Defective DSB repair correlates with abnormal nuclear morphology and is improved with FTI treatment in Hutchinson-Gilford progeria syndrome fibroblasts. Exp Cell Res 316:2747-2759. http://dx.doi.org/10 .1016/j.yexcr.2010.05.015.
76. Redwood AB, Perkins SM, Vanderwaal RP, Feng Z, Biehl KJ, Gonzalez-Suarez I, Morgado-Palacin L, Shi W, Sage J, Roti-Roti JL, Stewart CL, Zhang J, Gonzalo S. 2011. A dual role for A-type lamins in DNA doublestrand break repair. Cell Cycle 10:2549-2560. http://dx.doi.org/10.4161 /cc.10.15.16531.
77. Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadinanos J, Lopez-Otin C, Tse HF, Hutchison C, Chen J, Cao Y, Cheah KS, Tryggvason K, Zhou Z. 2005. Genomic instability in laminopathy-based premature aging. Nat Med 11:780-785. http://dx.doi.org/10.1038/nm1266.
78. Ondov BD, Bergman NH, Phillippy AM. 2011. Interactive metagenomic visualization in a Web browser.BMCBioinformatics 12:385. http://dx.doi .org/10.1186/1471-2105-12-385.
79. Kanehisa M. 2002. The KEGG database. Novartis Found Symp 247:91- 101. http://dx.doi.org/10.1002/0470857897.ch8.