Mechanistic Modelling and Bayesian Inference Elucidates the Variable Dynamics of Double-Strand Break Repair

PLoS Computational Biology

Volumn 12, Issue 10, 2016, Pages

  Woods, Mae L ^a   Barnes, Chris P ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BAYESIAN NETWORKS; BIOLOGY; DNA; DYNAMICS; INFERENCE ENGINES; IONIZING RADIATION; JOINING;

BAYESIAN INFERENCE; DNA DOUBLE STRAND BREAKS; DNA REPLICATIONS; DOUBLE STRAND BREAK REPAIR; DOUBLE STRAND BREAKS; MECHANISTIC MODELS; MODEL INFERENCE; NONHOMOLOGOUS END JOINING; REPAIR MECHANISM; VARIABLE DYNAMICS;

REPAIR;

ALGORITHM; ARTICLE; BAYES THEOREM; CALCULATION; DNA REPAIR; DNA STRAND BREAKAGE; MATHEMATICAL ANALYSIS; PREDICTION; SIMULATION; STOCHASTIC MODEL; BIOLOGICAL MODEL; CHEMICAL MODEL; COMPUTER SIMULATION; DOUBLE STRANDED DNA BREAK; GENETICS; IONIZING RADIATION; MOLECULAR MODEL; PHYSIOLOGY; RADIATION DOSE; RADIATION RESPONSE; STATISTICAL MODEL;

DNA;

BAYES THEOREM; COMPUTER SIMULATION; DNA; DNA BREAKS, DOUBLE-STRANDED; DNA REPAIR; MODELS, CHEMICAL; MODELS, GENETIC; MODELS, MOLECULAR; MODELS, STATISTICAL; RADIATION DOSAGE; RADIATION, IONIZING;

EID: 84994103586     PISSN: 1553734X     EISSN: 15537358     Source Type: Journal    
DOI: 10.1371/journal.pcbi.1005131     Document Type: Article

References (80)

1. Mizuuchi K, Fisher LM, O’Dea MH, Gellert M, DNA gyrase action involves the introduction of transient double-strand breaks into DNA. Proc Natl Acad Sci U S A. 1980;77(4):1847–1851. doi: 10.1073/pnas.77.4.18476246508
2. Freifelder D, Lethal Changes in Bacteriophage DNA Produced by X-Rays. Radiation Research Supplement. 1966;6:pp. 80–96. doi: 10.2307/35835525957644
3. Difilippantonio MJ, Zhu J, Chen HT, Meffre E, Nussenzweig MC, Max EE, et al. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature. 2000mar;404(6777):510–514. doi: 10.1038/3500667010761921
4. Jasin M, Richardson C, Frequent chromosomal translocations induced by DNA double-strand breaks. Nature. 2000;405(6787):697–700. doi: 10.1038/3501509710864328
5. Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A, Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination. Nature. 2015;518(7538):254–257. Available from: http://dx.doi.org/10.1038/nature14157. 25642960
6. Sugawara N, Haber JE, Characterization of double-strand break-induced recombination: homology requirements and single-stranded DNA formation. Molecular and Cellular Biology. 1992;12(2):563–575. doi: 10.1128/MCB.12.2.5631732731
7. Moore JK, Haber JE, Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae. Molecular and Cellular Biology. 1996;16(5):2164–73. doi: 10.1128/MCB.16.5.21648628283
8. Moynahan ME, Jasin M, Loss of heterozygosity induced by a chromosomal double strand break. Proceedings of the National Academy of Sciences. 1997;94(17):8988–8993. doi: 10.1073/pnas.94.17.89889256422
9. Budman J, Chu G, Processing of DNA for nonhomologous end-joining by cell-free extract. The EMBO Journal. 2005;24(4):849–860. doi: 10.1038/sj.emboj.760056315692565
10. Rathmell WK, Chu G, Involvement of the Ku autoantigen in the cellular response to DNA double-strand breaks. Proceedings of the National Academy of Sciences. 1994;91(16):7623–7627. doi: 10.1073/pnas.91.16.76238052631
11. Liang F, Romanienko PJ, Weaver DT, Jeggo PA, Jasin M, Chromosomal double-strand break repair in Ku80-deficient cells. Proceedings of the National Academy of Sciences. 1996;93(17):8929–8933. doi: 10.1073/pnas.93.17.89298799130
12. Hammarsten O, Chu G, DNA-dependent protein kinase: DNA binding and activation in the absence of Ku. Proceedings of the National Academy of Sciences. 1998;95(2):525–530. doi: 10.1073/pnas.95.2.5259435225
13. Ma Y, Pannicke U, Schwarz K, Lieber MR, Hairpin Opening and Overhang Processing by an Artemis/DNA-Dependent Protein Kinase Complex in Nonhomologous End Joining and V(D)J Recombination. Cell. 2002;108(6):781–794. doi: 10.1016/S0092-8674(02)00671-211955432
14. Grawunder U, Wilm M, Wu X, Kulesza P, Wilson TE, Mann M, et al. Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature;388(6641):492–495. doi: 10.1038/413589242410
15. DiBiase SJ, Zeng ZC, Chen R, Hyslop T, Curran WJ, Iliakis G, DNA-dependent Protein Kinase Stimulates an Independently Active, Nonhomologous, End-Joining Apparatus. Cancer Research. 2000;60(5):1245–1253. 10728683
16. Beucher A, Birraux J, Tchouandong L, Barton O, Shibata A, Conrad S, et al. ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2. The EMBO Journal. 2009;28(21):3413–3427. doi: 10.1038/emboj.2009.27619779458
17. Ochi T, Blackford AN, Coates J, Jhujh S, Mehmood S, Tamura N, et al. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science. 2015;347(6218):185–188. Available from: http://www.sciencemag.org/content/347/6218/185.abstract. doi: 10.1126/science.126197125574025
18. Pâques F, Haber JE, Multiple Pathways of Recombination Induced by Double-Strand Breaks in Saccharomyces cerevisiae. Microbiology and Molecular Biology Reviews. 1999;63(2):349–404. 10357855
19. Lin FL, Sperle K, Sternberg N, Model for homologous recombination during transfer of DNA into mouse L cells: role for DNA ends in the recombination process. Molecular and Cellular Biology. 1984;4(6):1020–1034. doi: 10.1128/MCB.4.6.10206330525
20. Lin FL, Sperle K, Sternberg N, Recombination in mouse L cells between DNA introduced into cells and homologous chromosomal sequences. Proc Natl Acad Sci. 1985;82(5):1391–5. doi: 10.1073/pnas.82.5.13913856266
21. Deng SK, Gibb B, de Almeida MJ, Greene EC, Symington LS, RPA antagonizes microhomology-mediated repair of DNA double-strand breaks. Nat Struct Mol Biol. 2014;21(4):405–412. Available from: http://dx.doi.org/10.1038/nsmb.2786. 24608368
22. Xiong X, Du Z, Wang Y, Feng Z, Fan P, Yan C, et al. 53BP1 promotes microhomology-mediated end-joining in G1-phase cells. Nucleic Acids Research. 2015;43(3):1659–1670. Available from: http://nar.oxfordjournals.org/content/43/3/1659.abstract. doi: 10.1093/nar/gku140625586219
23. Mansour WY, Rhein T, Dahm-Daphi J, The alternative end-joining pathway for repair of DNA double-strand breaks requires PARP1 but is not dependent upon microhomologies. Nucleic Acids Research. 2010;38(18):6065–6077. Available from: http://nar.oxfordjournals.org/content/38/18/6065.abstract. doi: 10.1093/nar/gkq38720483915
24. Wang M, Wu W, Wu W, Rosidi B, Zhang L, Wang H, et al. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Research. 2006;34(21):6170–6182. doi: 10.1093/nar/gkl84017088286
25. Schipler A, Iliakis G, DNA double-strand-break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice. Nucleic Acids Research. 2013;41(16):7589–7605. doi: 10.1093/nar/gkt55623804754
26. Vilenchik MM, Knudson AG, Endogenous DNA double-strand breaks: Production, fidelity of repair, and induction of cancer. Proceedings of the National Academy of Sciences. 2003;100(22):12871–12876. doi: 10.1073/pnas.213549810014566050
27. Branzei D, Foiani M, Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol. 2008;9(4):297–308. Available from: http://dx.doi.org/10.1038/nrm2351. 18285803
28. Karanam K, Kafri R, Loewer A, Lahav G, Quantitative Live Cell Imaging Reveals a Gradual Shift between DNA Repair Mechanisms and a Maximal Use of HR in Mid S Phase. Molecular Cell. 2012;47(2):320–329. doi: 10.1016/j.molcel.2012.05.05222841003
29. Hentges P, Waller H, Reis CC, Ferreira MG, Doherty AJ, Cdk1 Restrains NHEJ through Phosphorylation of XRCC4-like Factor Xlf1. Cell Reports. 2015;9(6):2011–2017. Available from: http://www.cell.com/cell-reports/abstract/S2211-1247(14)01010-9. doi: 10.1016/j.celrep.2014.11.04425533340
30. Trujillo KM, Yuan SSF, Lee EYHP, Sung P, Nuclease Activities in a Complex of Human Recombination and DNA Repair Factors Rad50, Mre11, and p95. Journal of Biological Chemistry. 1998;273(34):21447–21450. doi: 10.1074/jbc.273.34.214479705271
31. Deng X, Prakash A, Dhar K, Baia GS, Kolar C, Oakley GG, et al. Human Replication Protein A Rad52 Single Stranded DNA Complex: Stoichiometry and Evidence for Strand Transfer Regulation by Phosphorylation. Biochemistry. 2009;48(28):6633–6643. doi: 10.1021/bi900564k19530647
32. Mortensen UH, Bendixen C, Sunjevaric I, Rothstein R, DNA strand annealing is promoted by the yeast Rad52 protein. Proc Natl Acad Sci U S A. 1996;93(20):10729–34. doi: 10.1073/pnas.93.20.107298855248
33. Götlich B, Reichenberger S, Feldmann E, Pfeiffer P, Rejoining of DNA double-strand breaks in vitro by single-strand annealing. European Journal of Biochemistry. 1998;258(2):387–395. 9874203
34. Wang H, Zeng ZC, Bui TA, Sonoda E, Takata M, Takeda S, et al. Efficient rejoining of radiation-induced DNA double-strand breaks in vertebrate cells deficient in genes of the RAD52 epistasis group. Oncogene. 2001;20(18). doi: 10.1038/sj.onc.120435011402316
35. Fishman-Lobell J, Rudin N, Haber JE, Two alternative pathways of double-strand break repair that are kinetically separable and independently modulated. Molecular and Cellular Biology. 1992;12(3):1292–1303. doi: 10.1128/MCB.12.3.12921545810
36. Ma JL, Kim EM, Haber JE, Lee SE, Yeast Mre11 and Rad1 Proteins Define a Ku-Independent Mechanism To Repair Double-Strand Breaks Lacking Overlapping End Sequences. Molecular and Cellular Biology. 2003;23(23):8820–8828. Available from: http://mcb.asm.org/content/23/23/8820.abstract. doi: 10.1128/MCB.23.23.8820-8828.200314612421
37. Iliakis G, Backup pathways of NHEJ in cells of higher eukaryotes: Cell cycle dependence. Radiotherapy and Oncology. 2009;92(3):310–315. Special Issue on Molecular and Experimental Radiobiology Including papers from the 11th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology. Available from: http://www.sciencedirect.com/science/article/pii/S0167814009003351. doi: 10.1016/j.radonc.2009.06.02419604590
38. Wang H, Perrault AR, Takeda Y, Qin W, Wang H, Iliakis G, Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Research. 2003;31(18):5377–5388. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC203313/. doi: 10.1093/nar/gkg72812954774
39. Mladenov E, Magin S, Soni A, Iliakis G, DNA Double-Strand Break Repair as determinant of cellular radiosensitivity to killing and target in radiation therapy. Frontiers in Oncology. 2013;3(113). doi: 10.3389/fonc.2013.0011323675572
40. Decottignies A, Alternative end-joining mechanisms: a historical perspective. Frontiers in Genetics. 2013;4(48). Available from: http://www.frontiersin.org/cancer_genetics/10.3389/fgene.2013.00048/abstract. doi: 10.3389/fgene.2013.0004823565119
41. Zhang Y, Jasin M, An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway. Nat Struct Mol Biol. 2011;18(1):80–84. doi: 10.1038/nsmb.194021131978
42. Audebert M, Salles B, Calsou P, Involvement of Poly(ADP-ribose) Polymerase-1 and XRCC1/DNA Ligase III in an Alternative Route for DNA Double-strand Breaks Rejoining. Journal of Biological Chemistry. 2004;279(53):55117–55126. doi: 10.1074/jbc.M40452420015498778
43. Liang L, Deng L, Nguyen SC, Zhao X, Maulion CD, Shao C, et al. Human DNA ligases I and III, but not ligase IV, are required for microhomology-mediated end joining of DNA double-strand breaks. Nucleic Acids Research. 2008;36(10):3297–3310. doi: 10.1093/nar/gkn18418440984
44. Soni A, Siemann M, Grabos M, Murmann T, Pantelias GE, Iliakis G, Requirement for Parp-1 and DNA ligases 1 or 3 but not of Xrcc1 in chromosomal translocation formation by backup end joining. Nucleic Acids Research. 2014;42(10):6380–6392. Available from: http://nar.oxfordjournals.org/content/42/10/6380.abstract. doi: 10.1093/nar/gku29824748665
45. Howard SM, Yanez DA, Stark JM, DNA Damage Response Factors from Diverse Pathways, Including DNA Crosslink Repair, Mediate Alternative End Joining. PLoS Genet. 2015;11(1):e1004943. Available from: http://dx.doi.org/10.1371%2Fjournal.pgen.1004943. 25629353
46. L M, G I, Kinetics of DNA double-strand break repair throughout the cell cycle as assayed by pulsed field gel electrophoresis in CHO cells. Int J Radiat Biol. 1991;59(1). 1677379
47. Verbruggen P, Heinemann T, Manders E, von Bornstaedt G, van Driel R, Höfer T, Robustness of DNA Repair through Collective Rate Control. PLoS Comput Biol. 2014;10(1):e1003438. doi: 10.1371/journal.pcbi.100343824499930
48. Cucinotta FA, Pluth JM, Anderson JA, Harper JV, O’Neill P, Biochemical Kinetics Model of DSB Repair and Induction of gamma-H2AX Foci by Non-homologous End Joining. Radiation Research. 2008;169(2):214–222. doi: 10.1667/RR1035.118220463
49. Taleei R, Weinfeld M, Nikjoo H, Single strand annealing mathematical model for double strand break repair. journal of Molecular Engineering and Systems Biology. 2012;1(1). doi: 10.7243/2050-1412-1-1
50. Taleei R, Nikjoo H, The Non-homologous End-Joining (NHEJ) Pathway for the Repair of DNA Double-Strand Breaks: I. A Mathematical Model. Radiation Research. 2013;179(5):530–539. doi: 10.1667/RR3123.123560635
51. Taleei R, Weinfeld M, Nikjoo H, A kinetic model of single-strand annealing for the repair of DNA double-strand breaks. Radiation Protection Dosimetry. 2011;143(2–4):191–195. doi: 10.1093/rpd/ncq53521183536
52. Belov OV, Krasavin EA, Lyashko MS, Batmunkh M, Sweilam NH, A quantitative model of the major pathways for radiation-induced DNA double-strand break repair. Journal of Theoretical Biology. 2015;366(0):115–130. Available from: http://www.sciencedirect.com/science/article/pii/S0022519314005633. doi: 10.1016/j.jtbi.2014.09.02425261728
53. Friedland W, Kundrát P, Jacob P, Stochastic modelling of DSB repair after photon and ion irradiation. International Journal of Radiation Biology. 2012;88(1–2):129–136. doi: 10.3109/09553002.2011.61140421823824
54. Friedland W, Jacob P, Kundrát P, Stochastic Simulation of DNA Double-Strand Break Repair by Non-homologous End Joining Based on Track Structure Calculations. Radiation Research. 2013;173(5):677–688. doi: 10.1667/RR1965.120426668
55. Li Y, Qian H, Wang Y, Cucinotta FA, A Stochastic Model of DNA Fragments Rejoining. PLoS ONE. 2012;7(9):e44293. doi: 10.1371/journal.pone.004429323028515
56. Bodgi L, Foray N, On the coherence between mathematical models of DSB repair and physiological reality. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2014;761:48–49. Available from: http://www.sciencedirect.com/science/article/pii/S1383571814000047. doi: 10.1016/j.mrgentox.2014.01.00324440722
57. Taleei R, Girard PM, Nikjoo H, DSB repair model for mammalian cells in early S and G1 phases of the cell cycle: Application to damage induced by ionizing radiation of different quality. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2015;779:5–14. doi: 10.1016/j.mrgentox.2015.01.00725813721
58. Taleei R, Nikjoo H, Response to the Letter of Bodgi and Foray: On the coherence between mathematical models of DSB repair and physiological reality. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2014;761:50–52. doi: 10.1016/j.mrgentox.2014.01.00124440803
59. Taleei R, Girard PM, Sankaranarayanan K, Nikjoo H, The Non-homologous End-Joining (NHEJ) Mathematical Model for the Repair of Double-Strand Breaks: II. Application to Damage Induced by Ultrasoft X Rays and Low-Energy Electrons. Radiation Research. 2013 2015/11/02;179(5):540–548. Available from: http://dx.doi.org/10.1667/RR3124.1. 23560631
60. Nikjoo H, Uehara S, Emfietzoglou D, Cucinotta FA, Track-structure codes in radiation research. Radiation Measurements. 2006;41(9–10):1052–1074. Space Radiation Transport, Shielding, and Risk Assessment Models. Available from: http://www.sciencedirect.com/science/article/pii/S1350448706001338. doi: 10.1016/j.radmeas.2006.02.001
61. Windhofer F, Wu W, Iliakis G, Low levels of DNA ligases III and IV sufficient for effective NHEJ. Journal of Cellular Physiology. 2007;213(2):475–483. doi: 10.1002/jcp.2112017492771
62. Wu W, Wang M, Wu W, Singh SK, Mussfeldt T, Iliakis G, Repair of radiation induced DNA double strand breaks by backup NHEJ is enhanced in G2. DNA Repair. 2008;7(2):329–338. doi: 10.1016/j.dnarep.2007.11.00818155970
63. Iliakis G, Wang H, Perrault AR, Boecker W, Rosidi B, Windhofer F, et al. Mechanisms of DNA double strand break repair and chromosome aberration formation. Cytogenetic and Genome Research. 2004;104(1–4):14–20. doi: 10.1159/00007746115162010
64. Zhang LY, Chen LS, Sun R, JI SJ, Ding YY, Wu J, et al. Effects of expression level of DNA repair-related genes involved in the NHEJ pathway on radiation-induced cognitive impairment. Journal of Radiation Research. 2013;54(2):235–242. Available from: http://jrr.oxfordjournals.org/content/54/2/235.abstract. doi: 10.1093/jrr/rrs09523135157
65. Gillespie DT, Exact stochastic simulation of coupled chemical reactions. J Phys Chem. 1977;81(25):2340–2361. doi: 10.1063/1.271025317411109
66. Toni T, Welch D, Strelkowa N, Ipsen A, Stumpf MPH, Approximate Bayesian computation scheme for parameter inference and model selection in dynamical systems. Journal of the Royal Society, Interface / the Royal Society. 2009;6(31):187–202. doi: 10.1098/rsif.2008.017219205079
67. Toni T, Stumpf MPH, Simulation-based model selection for dynamical systems in systems and population biology. Bioinformatics. 2010Jan;26(1):104–110. doi: 10.1093/bioinformatics/btp61919880371
68. Liepe J, Barnes C, Cule E, Erguler K, Kirk P, Toni T, et al. ABC-SysBio–approximate Bayesian computation in Python with GPU support. Bioinformatics. 2010;26(14):1797–1799. Available from: http://bioinformatics.oxfordjournals.org/content/26/14/1797.abstract. doi: 10.1093/bioinformatics/btq27820591907
69. Liepe J, Kirk P, Filippi S, Toni T, Barnes CP, Stumpf MPH, A framework for parameter estimation and model selection from experimental data in systems biology using approximate Bayesian computation. Nature protocols. 2014;9(2):439–456. doi: 10.1038/nprot.2014.02524457334
70. Spiegelhalter DJ, Best NG, Carlin BP, Bayesian measures of model complexity and fit. Journal of the Royal Statistical Society, Series B. 2002;. doi: 10.1111/1467-9868.00353
71. Akaike H, A new look at the statistical model identification. Automatic Control, IEEE Transactions on. 1974Dec;19(6):716–723. Available from: http://dx.doi.org/10.1109/tac.1974.1100705.
72. Olivier F, Guillaume L, Deviance Information Criteria for Model Selection in Approximate Bayesian Computation. Statistical Applications in Genetics and Molecular Biology. 2011;10(1):1–25. Available from: http://EconPapers.repec.org/RePEc:bpj:sagmbi:v:10:y:2011:i:1:n:33.
73. Shibata A, Conrad S, Birraux J, Geuting V, Barton O, Ismail A, et al. Factors determining DNA double-strand break repair pathway choice in G2 phase. The EMBO Journal. 2011;30(6):1079–1092. doi: 10.1038/emboj.2011.2721317870
74. Haince JF, McDonald D, Rodrigue A, Dery U, Masson JY, Hendzel MJ, et al. PARP1-dependent Kinetics of Recruitment of MRE11 and NBS1 Proteins to Multiple DNA Damage Sites. Journal of Biological Chemistry. 2008;283(2):1197–1208. Available from: http://www.jbc.org/content/283/2/1197.abstract. doi: 10.1074/jbc.M70673420018025084
75. Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MIR, et al. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature. 2015;518(7538):258–262. Available from: http://dx.doi.org/10.1038/nature14184. 25642963
76. Cho NW, Greenberg RA, DNA repair: Familiar ends with alternative endings. Nature. 2015;518(7538):174–176. Available from: http://dx.doi.org/10.1038/nature14200. 25642961
77. Pitroda SP, Pashtan IM, Logan HL, Budke B, Darga TE, Weichselbaum RR, et al. DNA Repair Pathway Gene Expression Score Correlates with Repair Proficiency and Tumor Sensitivity to Chemotherapy. Science Translational Medicine. 2014;6(229):229ra42–229ra42. Available from: http://stm.sciencemag.org/content/6/229/229ra42. doi: 10.1126/scitranslmed.300829124670686
78. Dobbs TA, Palmer P, Maniou Z, Lomax ME, O’Neill P, Interplay of two major repair pathways in the processing of complex double-strand DNA breaks. DNA Repair. 2008;7(8):1372–1383. Available from: http://www.sciencedirect.com/science/article/pii/S1568786408001845. doi: 10.1016/j.dnarep.2008.05.00118571480
79. Sutherland BM, Bennett PV, Sidorkina O, Laval J, Clustered Damages and Total Lesions Induced in DNA by Ionizing Radiation: Oxidized Bases and Strand Breaks. Biochemistry. 2000;39(27):8026–8031. doi: 10.1021/bi992798910891084
80. Woodbine L, Brunton H, Goodarzi AA, Shibata A, Jeggo PA, Endogenously induced DNA double strand breaks arise in heterochromatic DNA regions and require ataxia telangiectasia mutated and Artemis for their repair. Nucleic Acids Research. 2011;39(16):6986–6997. Available from: http://nar.oxfordjournals.org/content/39/16/6986.abstract. doi: 10.1093/nar/gkr33121596788