Nbs1 ChIP-Seq Identifies Off-Target DNA Double-Strand Breaks Induced by AID in Activated Splenic B Cells

1. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, et al. (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102: 553–563. 11007474

2. Revy P, Muto T, Levy Y, Geissmann F, Plebani A, et al. (2000) Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102: 565–575. 11007475

3. Petersen-Mahrt SK, Harris RS, Neuberger MS (2002) AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418: 99–104. 12097915

4. Rada C, Williams GT, Nilsen H, Barnes DE, Lindahl T, et al. (2002) Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr Biol 12: 1748–1755. 12401169

5. Stavnezer J, Schrader CE (2014) IgH Chain Class Switch Recombination: Mechanism and Regulation. J Immunol 193: 5370–5378. doi: 10.4049/jimmunol.1401849 25411432

6. Shen HM, Peters A, Baron B, Zhu X, Storb U (1998) Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280: 1750–1752. 9624052

7. Pasqualucci L, Migliazza A, Fracchiolla N, William C, Neri A, et al. (1998) BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad Sci U S A 95: 11816–11821. 9751748

8. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, et al. (2001) Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412: 341–346. 11460166

9. Liu M, Duke JL, Richter DJ, Vinuesa CG, Goodnow CC, et al. (2008) Two levels of protection for the B cell genome during somatic hypermutation. Nature 451: 841–845. doi: 10.1038/nature06547 18273020

10. Pavri R, Gazumyan A, Jankovic M, Di Virgilio M, Klein I, et al. (2010) Activation-induced cytidine deaminase targets DNA at sites of RNA polymerase II stalling by interaction with Spt5. Cell 143: 122–133. doi: 10.1016/j.cell.2010.09.017 20887897

11. Duke JL, Liu M, Yaari G, Khalil AM, Tomayko MM, et al. (2013) Multiple transcription factor binding sites predict AID targeting in non-Ig genes. J Immunol 190: 3878–3888. doi: 10.4049/jimmunol.1202547 23514741

12. Dorsett Y, Robbiani DF, Jankovic M, Reina-San-Martin B, Eisenreich TR, et al. (2007) A role for AID in chromosome translocations between c-myc and the IgH variable region. J Exp Med 204: 2225–2232. 17724134

13. Robbiani DF, Bothmer A, Callen E, Reina-San-Martin B, Dorsett Y, et al. (2008) AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations. Cell 135: 1028–1038. doi: 10.1016/j.cell.2008.09.062 19070574

14. Hasham MG, Donghia NM, Coffey E, Maynard J, Snow KJ, et al. (2010) Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination. Nat Immunol 11: 820–826. doi: 10.1038/ni.1909 20657597

15. Staszewski O, Baker RE, Ucher AJ, Martier R, Stavnezer J, et al. (2011) Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells. Mol Cell 41: 232–242. doi: 10.1016/j.molcel.2011.01.007 21255732

16. Yamane A, Resch W, Kuo N, Kuchen S, Li Z, et al. (2011) Deep-sequencing identification of the genomic targets of the cytidine deaminase AID and its cofactor RPA in B lymphocytes. Nat Immunol 12: 62–69. doi: 10.1038/ni.1964 21113164

17. Klein IA, Resch W, Jankovic M, Oliveira T, Yamane A, et al. (2011) Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell 147: 95–106. doi: 10.1016/j.cell.2011.07.048 21962510

18. Chiarle R, Zhang Y, Frock RL, Lewis SM, Molinie B, et al. (2011) Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell 147: 107–119. doi: 10.1016/j.cell.2011.07.049 21962511

19. Yamane A, Robbiani DF, Resch W, Bothmer A, Nakahashi H, et al. (2013) RPA accumulation during class switch recombination represents 5'-3' DNA-end resection during the S-G2/M phase of the cell cycle. Cell Rep 3: 138–147. doi: 10.1016/j.celrep.2012.12.006 23291097

20. Meng FL, Du Z, Federation A, Hu J, Wang Q, et al. (2014) Convergent Transcription at Intragenic Super-Enhancers Targets AID-Initiated Genomic Instability. Cell 159: 1538–1548. doi: 10.1016/j.cell.2014.11.014 25483776

21. Qian J, Wang Q, Dose M, Pruett N, Kieffer-Kwon KR, et al. (2014) B Cell Super-Enhancers and Regulatory Clusters Recruit AID Tumorigenic Activity. Cell 159: 1524–1537. doi: 10.1016/j.cell.2014.11.013 25483777

22. Wang Q, Oliveira T, Jankovic M, Silva IT, Hakim O, et al. (2014) Epigenetic targeting of activation-induced cytidine deaminase. Proc Natl Acad Sci U S A 111: 18667–18672. doi: 10.1073/pnas.1420575111 25512519

23. Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, et al. (2008) Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A 105: 13520–13525. doi: 10.1073/pnas.0804295105 18765795

24. Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, et al. (2007) Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med 13: 470–476. 17401375

25. Lin C, Yang L, Tanasa B, Hutt K, Ju BG, et al. (2009) Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 139: 1069–1083. doi: 10.1016/j.cell.2009.11.030 19962179

26. Petersen S, Casellas R, Reina-San-Martin B, Chen HT, Difilippantonio MJ, et al. (2001) AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching. Nature 414: 660–665. 11740565

27. Manis JP, Tian M, Alt FW (2002) Mechanism and control of class-switch recombination. Trends Immunol 23: 31–39. 11801452

28. Casellas R, Nussenzweig A, Wuerffel R, Pelanda R, Reichlin A, et al. (1998) Ku80 is required for immunoglobulin isotype switching. EMBO J 17: 2404–2411. 9545251

29. Cortizas EM, Zahn A, Hajjar ME, Patenaude AM, Di Noia JM, et al. (2013) Alternative End-Joining and Classical Nonhomologous End-Joining Pathways Repair Different Types of Double-Strand Breaks during Class-Switch Recombination. J Immunol 191: 5751–5763. doi: 10.4049/jimmunol.1301300 24146042

30. Dinkelmann M, Spehalski E, Stoneham T, Buis J, Wu Y, et al. (2009) Multiple functions of MRN in end-joining pathways during isotype class switching. Nat Struct Mol Biol 16: 808–813. doi: 10.1038/nsmb.1639 19633670

31. Lee-Theilen M, Matthews AJ, Kelly D, Zheng S, Chaudhuri J (2011) CtIP promotes microhomology-mediated alternative end joining during class-switch recombination. Nat Struct Mol Biol 18: 75–79. doi: 10.1038/nsmb.1942 21131982

32. McVey M, Lee SE (2008) MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings. Trends Genet 24: 529–538. doi: 10.1016/j.tig.2008.08.007 18809224

33. Cannavo E, Cejka P (2014) Sae2 promotes dsDNA endonuclease activity within Mre11-Rad50-Xrs2 to resect DNA breaks. Nature 514: 122–125. doi: 10.1038/nature13771 25231868

34. Truong LN, Li Y, Shi LZ, Hwang PY, He J, et al. (2013) Microhomology-mediated End Joining and Homologous Recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells. Proc Natl Acad Sci U S A 110: 7720–7725. doi: 10.1073/pnas.1213431110 23610439

35. Balestrini A, Ristic D, Dionne I, Liu XZ, Wyman C, et al. (2013) The Ku heterodimer and the metabolism of single-ended DNA double-strand breaks. Cell Rep 3: 2033–2045. doi: 10.1016/j.celrep.2013.05.026 23770241

36. Feng L, Chen J (2012) The E3 ligase RNF8 regulates KU80 removal and NHEJ repair. Nat Struct Mol Biol 19: 201–206. doi: 10.1038/nsmb.2211 22266820

37. Boboila C, Jankovic M, Yan CT, Wang JH, Wesemann DR, et al. (2010) Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70. Proc Natl Acad Sci U S A 107: 3034–3039. doi: 10.1073/pnas.0915067107 20133803

38. Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, et al. (2007) IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449: 478–482. 17713479

39. Zhang Y, Jasin M (2011) An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway. Nat Struct Mol Biol 18: 80–84. doi: 10.1038/nsmb.1940 21131978

40. Shibata A, Moiani D, Arvai AS, Perry J, Harding SM, et al. (2014) DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Mol Cell 53: 7–18. doi: 10.1016/j.molcel.2013.11.003 24316220

41. Shibata A, Conrad S, Birraux J, Geuting V, Barton O, et al. (2011) Factors determining DNA double-strand break repair pathway choice in G2 phase. EMBO J 30: 1079–1092. doi: 10.1038/emboj.2011.27 21317870

42. Schrader CE, Linehan EK, Mochegova SN, Woodland RT, Stavnezer J (2005) Inducible DNA breaks in Ig S regions are dependent upon AID and UNG. J Exp Med 202: 561–568. 16103411

43. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, et al. (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38: 576–589. doi: 10.1016/j.molcel.2010.05.004 20513432

44. Barreto V, Reina-San-Martin B, Ramiro AR, McBride KM, Nussenzweig MC (2003) C-terminal deletion of AID uncouples class switch recombination from somatic hypermutation and gene conversion. Mol Cell 12: 501–508. 14536088

45. Schrader CE, Guikema JE, Linehan EK, Selsing E, Stavnezer J (2007) Activation-induced cytidine deaminase-dependent DNA breaks in class switch recombination occur during G1 phase of the cell cycle and depend upon mismatch repair. J Immunol 179: 6064–6071. 17947680

46. Khair L, Guikema JE, Linehan EK, Ucher AJ, Leus NG, et al. (2014) ATM Increases Activation-Induced Cytidine Deaminase Activity at Downstream S Regions during Class-Switch Recombination. J Immunol 192: 4887–4896. doi: 10.4049/jimmunol.1303481 24729610

47. Schrader CE, Bradley SP, Vardo J, Mochegova SN, Flanagan E, et al. (2003) Mutations occur in the Ig Sμ region but rarely in Sγ regions prior to class switch recombination. Embo J 22: 5893–5903. 14592986

48. Ucher AJ, Ranjit S, Kadungure T, Linehan EK, Khair L, et al. (2014) Mismatch Repair Proteins and AID Activity Are Required for the Dominant Negative Function of C-Terminally Deleted AID in Class Switching. J Immunol 193: 1440–1450. doi: 10.4049/jimmunol.1400365 24973444

49. Hogenbirk MA, Velds A, Kerkhoven RM, Jacobs H (2012) Reassessing genomic targeting of AID. Nat Immunol 13: 797–798; author reply 798–800. doi: 10.1038/ni.2367 22910380

50. Rajagopal D, Maul RW, Ghosh A, Chakraborty T, Khamlichi AA, et al. (2009) Immunoglobulin switch mu sequence causes RNA polymerase II accumulation and reduces dA hypermutation. J Exp Med 206: 1237–1244. doi: 10.1084/jem.20082514 19433618

51. Wang L, Wuerffel R, Feldman S, Khamlichi AA, Kenter AL (2009) S region sequence, RNA polymerase II, and histone modifications create chromatin accessibility during class switch recombination. J Exp Med 206: 1817–1830. doi: 10.1084/jem.20081678 19596805

52. Skourti-Stathaki K, Proudfoot NJ, Gromak N (2011) Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol Cell 42: 794–805. doi: 10.1016/j.molcel.2011.04.026 21700224

53. Sharbeen G, Yee CW, Smith AL, Jolly CJ (2012) Ectopic restriction of DNA repair reveals that UNG2 excises AID-induced uracils predominantly or exclusively during G1 phase. J Exp Med 209: 965–974. doi: 10.1084/jem.20112379 22529268

54. Hasham MG, Snow KJ, Donghia NM, Branca JA, Lessard MD, et al. (2012) Activation-induced cytidine deaminase-initiated off-target DNA breaks are detected and resolved during S phase. J Immunol 189: 2374–2382. doi: 10.4049/jimmunol.1200414 22826323

55. Lamont KR, Hasham MG, Donghia NM, Branca J, Chavaree M, et al. (2013) Attenuating homologous recombination stimulates an AID-induced antileukemic effect. J Exp Med 210: 1021–1033. 23589568

56. Costantino L, Sotiriou SK, Rantala JK, Magin S, Mladenov E, et al. (2014) Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science 343: 88–91. doi: 10.1126/science.1243211 24310611

57. Howard SM, Yanez DA, Stark JM (2015) DNA damage response factors from diverse pathways, including DNA crosslink repair, mediate alternative end joining. PLoS Genet 11: e1004943. doi: 10.1371/journal.pgen.1004943 25629353

58. Min I, Schrader C, Vardo J, D'Avirro N, Luby T, et al. (2003) The Sm tandem repeat region is critical for isotype switching in the absence of Msh2. Immunity 19: 515–524. 14563316

59. Stavnezer J, Guikema JEJ, Schrader CE (2008) Mechanism and regulation of class switch recombination. Ann Rev Immunol 26: 261–292.

60. Pena-Diaz J, Bregenhorn S, Ghodgaonkar M, Follonier C, Artola-Boran M, et al. (2012) Noncanonical mismatch repair as a source of genomic instability in human cells. Mol Cell 47: 669–680. doi: 10.1016/j.molcel.2012.07.006 22864113

61. Bak ST, Sakellariou D, Pena-Diaz J (2014) The dual nature of mismatch repair as antimutator and mutator: for better or for worse. Front Genet 5: 287. doi: 10.3389/fgene.2014.00287 25191341

62. de Miranda NF, Peng R, Georgiou K, Wu C, Falk Sorqvist E, et al. (2013) DNA repair genes are selectively mutated in diffuse large B cell lymphomas. J Exp Med 210: 1729–1742. doi: 10.1084/jem.20122842 23960188

63. DeWind N, Dekker M, Berns A, Radman M, TeRiele H (1995) Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82: 321–330. 7628020

64. Edelmann W, Yang K, Umar A, Heyer J, Lau K, et al. (1997) Mutation in the mismatch repair gene Msh6 causes cancer susceptibility. Cell 91: 467–477. 9390556

65. Berkovich E, Monnat RJ Jr., Kastan MB (2007) Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nat Cell Biol 9: 683–690. 17486112

66. Nordheim A, Rich A (1983) The sequence (dC-dA)n X (dG-dT)n forms left-handed Z-DNA in negatively supercoiled plasmids. Proc Natl Acad Sci U S A 80: 1821–1825. 6572943

67. Ho PS (1994) The non-B-DNA structure of d(CA/TG)n does not differ from that of Z-DNA. Proc Natl Acad Sci U S A 91: 9549–9553. 7937803

68. Ha SC, Lowenhaupt K, Rich A, Kim YG, Kim KK (2005) Crystal structure of a junction between B-DNA and Z-DNA reveals two extruded bases. Nature 437: 1183–1186. 16237447

69. Lu S, Wang G, Bacolla A, Zhao J, Spitser S, et al. (2015) Short Inverted Repeats Are Hotspots for Genetic Instability: Relevance to Cancer Genomes. Cell Rep 10: 1674–1680.

70. Rocha PP, Micsinai M, Kim JR, Hewitt SL, Souza PP, et al. (2012) Close proximity to Igh is a contributing factor to AID-mediated translocations. Mol Cell 47: 873–885. doi: 10.1016/j.molcel.2012.06.036 22864115

71. Gelmann EP, Psallidopoulos MC, Papas TS, Dalla-Favera R (1983) Identification of reciprocal translocation sites within the c-myc oncogene and immunoglobulin mu locus in a Burkitt lymphoma. Nature 306: 799–803. 6419123

72. Kuppers R (2005) Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 5: 251–262. 15803153

73. Janz S (2006) Myc translocations in B cell and plasma cell neoplasms. DNA Repair 5: 1213–1224. 16815105

74. Ramiro AR, Jankovic M, Callen E, Difilippantonio S, Chen HT, et al. (2006) Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 440: 105–109. 16400328

75. Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, et al. (2013) Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153: 320–334. doi: 10.1016/j.cell.2013.03.036 23582323

76. Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, et al. (2013) Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153: 307–319. doi: 10.1016/j.cell.2013.03.035 23582322

77. Basu U, Meng FL, Keim C, Grinstein V, Pefanis E, et al. (2011) The RNA Exosome Targets the AID Cytidine Deaminase to Both Strands of Transcribed Duplex DNA Substrates. Cell 144: 353–363. doi: 10.1016/j.cell.2011.01.001 21255825

78. Pefanis E, Wang J, Rothschild G, Lim J, Chao J, et al. (2014) Noncoding RNA transcription targets AID to divergently transcribed loci in B cells. Nature 514: 389–393. doi: 10.1038/nature13580 25119026

79. Wang G, Vasquez KM (2014) Impact of alternative DNA structures on DNA damage, DNA repair, and genetic instability. DNA Repair (Amst) 19: 143–151.

80. Wang G, Christensen LA, Vasquez KM (2006) Z-DNA-forming sequences generate large-scale deletions in mammalian cells. Proc Natl Acad Sci U S A 103: 2677–2682. 16473937

81. Kha DT, Wang G, Natrajan N, Harrison L, Vasquez KM (2010) Pathways for double-strand break repair in genetically unstable Z-DNA-forming sequences. J Mol Biol 398: 471–480. doi: 10.1016/j.jmb.2010.03.035 20347845

82. Wahba L, Amon JD, Koshland D, Vuica-Ross M (2011) RNase H and multiple RNA biogenesis factors cooperate to prevent RNA:DNA hybrids from generating genome instability. Mol Cell 44: 978–988. doi: 10.1016/j.molcel.2011.10.017 22195970

83. Sun J, Keim CD, Wang J, Kazadi D, Oliver PM, et al. (2013) E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells. Genes Dev 27: 1821–1833. doi: 10.1101/gad.210211.112 23964096

84. Pefanis E, Wang J, Rothschild G, Lim J, Kazadi D, et al. (2015) RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity. Cell 161: 774–789. doi: 10.1016/j.cell.2015.04.034 25957685

85. Sollier J, Stork CT, Garcia-Rubio ML, Paulsen RD, Aguilera A, et al. (2014) Transcription-coupled nucleotide excision repair factors promote R-loop-induced genome instability. Mol Cell 56: 777–785. doi: 10.1016/j.molcel.2014.10.020 25435140

86. Barlow JH, Faryabi RB, Callen E, Wong N, Malhowski A, et al. (2013) Identification of early replicating fragile sites that contribute to genome instability. Cell 152: 620–632. doi: 10.1016/j.cell.2013.01.006 23352430

87. Puc J, Kozbial P, Li W, Tan Y, Liu Z, et al. (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160: 367–380. doi: 10.1016/j.cell.2014.12.023 25619691

88. Guikema JE, Schrader CE, Brodsky MH, Linehan EK, Richards A, et al. (2010) p53 Represses Class Switch Recombination to IgG2a through Its Antioxidant Function. J Immunol 184: 6177–6187. doi: 10.4049/jimmunol.0904085 20483782

89. Reitmair AH, Cai JC, Bjerknes M, Redston M, Cheng H, et al. (1996) MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis. Cancer Res 56: 2922–2926. 8674041

90. Reitmair AH, Schmits R, Ewel A, Bapat B, Redston M, et al. (1995) MSH2 deficient mice are viable and susceptible to lymphoid tumours. Nat Genet 11: 64–70. 7550317

91. Ranjit S, Khair L, Linehan EK, Ucher AJ, Chakrabarti M, et al. (2011) AID binds cooperatively with UNG and Msh2-Msh6 to Ig switch regions dependent upon the AID C terminus. J Immunol 187: 2464–2475. doi: 10.4049/jimmunol.1101406 21804017

92. Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, et al. (2011) Integrative genomics viewer. Nat Biotechnol 29: 24–26. doi: 10.1038/nbt.1754 21221095

93. Nix DA, Courdy SJ, Boucher KM (2008) Empirical methods for controlling false positives and estimating confidence in ChIP-Seq peaks. BMC Bioinformatics 9: 523. doi: 10.1186/1471-2105-9-523 19061503

94. Benson G (1999) Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res 27: 573–580. 9862982

95. Zang C, Schones DE, Zeng C, Cui K, Zhao K, et al. (2009) A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 25: 1952–1958. doi: 10.1093/bioinformatics/btp340 19505939

96. Rice P, Longden I, Bleasby A (2000) EMBOSS: the European Molecular Biology Open Software Suite. Trends Genet 16: 276–277. 10827456