A Review of the mutational role of deaminases and the generation of a cognate molecular model to explain cancer mutation spectra Targeted Somatic Muation signatures in oncogenesis

Main Article Content

Robyn Alice Lindley


Recent developments in somatic mutation analyses have led to the discovery of codon-context targeted somatic mutation (TSM) signatures in cancer genomes: it is now known that deaminase mutation target sites are far more specific than previously thought. As this research provides novel insights into the deaminase origin of most of the somatic point mutations arising in cancer, a clear understanding of the mechanisms and processes involved will be valuable for molecular scientists as well as oncologists and cancer specialists in the clinic. This review will describe the basic research into the mechanism of antigen-driven somatic hypermutation of immunoglobulin variable genes (Ig SHM) that lead to the discovery of TSM signatures, and it will show that an Ig SHM-like signature is ubiquitous in the cancer exome. Most importantly, the data discussed in this review show that Ig SHM-like cancer-associated signatures are highly targeted to cytosine (C) and adenosine (A) nucleotides in a characteristic codon-context fashion. This review also provides an evidence-based model explaining how deaminases that cause mutations in cytosine and adenosine can gain access to their respective target motifs in genomic DNA (C-sites) and RNA (A-sites). It also highlights the clinical importance of understanding the molecular processes underpinning deaminase targeting for the development of new genomic diagnostics and drug discovery for pre-cancerous and clinically diagnosed cancer patients.

Keywords: deaminase, cancer, mutation signatures, Targeted Somatic Mutation, Somatic Hypermutation

Article Details

How to Cite
LINDLEY, Robyn Alice. A Review of the mutational role of deaminases and the generation of a cognate molecular model to explain cancer mutation spectra. Medical Research Archives, [S.l.], v. 8, n. 8, aug. 2020. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2177>. Date accessed: 03 mar. 2024. doi: https://doi.org/10.18103/mra.v8i8.2177.
Review Articles


1. Schoggins JW, Rice CM. Interferon-stimulated genes and their antiviral effector functions Curr Opin Virol. 1(6) (2011) 519 - 525. doi: 10.1016/j.coviro.2011.10.008.

2. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-421.
doi: 10.1038/nature12477.

3. Petljak M, Alexandrov LB, Brammeld JS, et al. Characterizing mutational signatures in human cancer cell lines reveals episodic APOBEC mutagenesis. Cell. 2019;176:1282-1294. doi: 10.20517/cdr.2019.005.

4. Alexandrov LB, Kim J, Haradhvala NJ, et al. The repertoire of mutational signatures in human cancer. Nature. 2020;578:94-101. doi: 10.1038/s41586-020-1943-3.

5. Rada C, Jarvis JM, Milstein C. AID-GFP chimeric protein increases hypermutation of Ig genes with no evidence of nuclear localization. Proc Natl Acad Sci. 2002;99:7003-7008. doi: 10.1073/pnas.092160999.

6. Refsland EW, Harris RS. The APOBEC3 family of retroelement restriction factors. Curr Top Microbiol Immunol. 2013;371:1-27.
doi: 10.1007/978-3-642-37765-5_1.

7. H.C. Smith HC, Bennett RP, Kizilyer A, et al. Functions and regulation of the APOBEC family of proteins. Cell Dev Biol. 2012;23:258 - 268. doi:10.1016/j.semcdb.2011.10.004.
8. Conticello SG.The AID/APOBEC family of nucleic acid mutators. Genome Biol. 2008;9:229. doi:10.1186/gb-2008-9-6-229.

9. Burns MB, Leonard B, Harris RS. APOBEC3B: Pathological consequences of an innate immune DNA Mutator Biomed J. 2015;38:102-110.
doi: 10.4103/2319-4170.148904

10. Salter JD, Bennett RP, Smith HC. The APOBEC Protein Family: United by Structure, Divergent in Function. Trends in Biochem Sciences. 2016;41(7):578‐594.
doi: 10.1016/j.tibs.2016.05.001.

11. Rogozin IB, Kolchanov NA. Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequences on mutagenesis. Biochimica et biophysica acta. 1992;1171:11-8. PMC6423074.

12. Beale RCL, Petersen-Mahrt SK, Watt IN, et al. Comparison of the different context-dependence of DNA deamination by APOBEC enzymes: correlation with mutation spectra in vivo. J Mol Biol. 2004;337:585-596.
doi: 10.1016/j.jmb.2004.01.046.

13. Roberts SA, Lawrence MS, Klimczak LJ, et al. An APOBEC Cytidine mutagenesis pattern is widespread in human cancers. Nat Genet. 2013;45:970-9766.
doi: 10.1038/ng.2702/.

14. Chan K, Roberts RA, Klimczak LJ, et al. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat Genet. 2015;47(9):1067-1072. doi: 10.1038/ng.3378.

15. Taylor BJM, Nik-Zainal S, Wu YL, et al, DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis. eLife. 2013;2: e00534.
doi: 10.7554/eLife.00534.

16. Logue FC, Bloch N, Dhuey E, et al. A DNA sequence recognition loop on APOBEC3A controls substrate specificity. PLoS ONE. 2014;9(5):e97062. doi:10.1371/journal.pone.0097062.

17. Chan K, Roberts SA, Klimczak LJ, et al. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat Genet. 2015;47(9):1067‐1072. doi:10.1038/ng.3378.

18. Leonard B, Hart SN, Burns MB, et al. APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma. Cancer Res. 2013;73:7222-7231.
doi: 10.1158/0008-5472.CAN-13-1753.

19. Burns MB, Lackey L, Carpenter MA, et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature. 2013a; 494:366-371. doi: 10.1038/nature11881.

20. Burns MB, Temiz NA, Harris RS. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat. Genet. 2013b;45:1-7. doi: 10.1038/ng.2701.

21. Langlois MA, Beale RC, Conticello SG, et al. Mutational comparison of the single-domained APOBEC3C and double-domained APOBEC3F/G anti-retroviral cytidine deaminases provides insight into their DNA target site specificities. Nucleic Acids Res. 2005;33(6):1913-1923.
doi: 10.1093/nar/gki343.

22. Dang Y, Wang X, Esselman WJ, et al. Identification of APOBEC3DE as another antiretroviral factor from the Human APOBEC Family. J. Virol. 80 (2006) 10522-10533. doi: 10.1128/JVI.01123-06.

23. Yu Q, Chen D, Konig R, et al. APOBEC3B and APOBEC3C are potent inhibitors of simian immunodeficiency virus replication. J of Biol Chem. 2004;279:53379-53386.
doi: 10.1074/jbc.M408802200.

24. Ehara H, Sekine SI. Architecture of the RNA polymerase II elongation complex: new insights into Spt4/5 and Elf1. Transcription. 2018;9(5):286‐291.
doi: 10.1080/21541264.2018.1454817.

25. Liddament MT, Brown WL, Schumacher AJ et al, APOBEC3F properties and hypermutation preferences indicate activity against HIV-1 in vivo.
Curr Biol. 2004;14:1385-1391.
doi: 10.1016/j.cub.2004.06.050.

26. Bishop KN, Holmes RK, Sheehy AM, et al. Cytidine deamination of retroviral DNA by diverse APOBEC proteins. Curr Biol. 2004;14:1392-1396.
doi: 10.1016/j.cub.2004.06.057.

27. Hache ́G, Liddament MT, Harris RS. 2005 The retroviral hypermutation specificity of APOBEC3F and APOBEC3G is governed by the C-terminal DNA cytosine deaminase domain. J Biol Chem. 2005;280:10920-10924. doi: 10.1074/jbc.M500382200.

28. E. Miyagi E, Brown CR, Opi, S, et al. Stably expressed APOBEC3F has negligible antiviral activity. J Virol. 2010;84:11067-11075.
doi: 10.1128/JVI.01249-10.

29. Henry M, Guetard D, Suspene R, et al. Genetic editing of HBV DNA by monodomain human APOBEC3 cytidine deaminases and the recombinant nature of APOBEC3G. PLoS ONE. 2009;4(1):e4277.
doi: 10.1371/journal.pone.0004277.

30. Harari A., Ooms M, Mulder, LC, et al. Polymorphisms and splice variants influence the antiretroviral activity of human APOBEC3H. J Virol. 2009;83:295-303. doi: 10.1128/JVI.01665-08.

31. Sowden M, Hamm JK, Smith HC. Overexpression of APOBEC-1 results in mooring sequence-dependent promiscuous RNA editing. J Biol Chem. 1996;271:3011-3017. http://www.jbc.org/content/271/6/3011.long.

32. Blanc V, Park E, Schaefer S, et al. Genome-wide identification and functional analysis of Apobec-1-mediated C-to-U RNA editing in mouse small intestine and liver. Genome Biol. 2014;15(6):R79. doi: 10.1186/gb-2014-15-6-r79.

33. Sharma S, Patnaik SK, Taggart, RT et al. APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages. Nat Commun. 2015;6:6881.
doi: 10.1038/ncomms7881.

34. Sharma S, Patnaik SK, Kemera Z, et al. 2016 Transient overexpression of exogenous APOBEC3A causes C-to-U RNA editing of thousands of genes. RNA Biol. 2016;14:603-610. doi: 10.1080/15476286.2016.1184387.

35. Rosenberg BR, Hamilton CE, Mwangi MM, et al. Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA editing targets in transcript 3′ UTRs. Nat Struct Mol Biol. 2011;18:230–236.
doi: 10.1038/nsmb.1975.

36. Alseth I, Dalhus B, Bjøras M. Inosine in DNA and RNA. Curr Opin Genet Dev. 2014;26:116-123.
doi: 10.1016/j.gde.2014.07.008.

37. Koning FA, Newman ENC, Kim E-Y, et al. Defining APOBEC3 expression patterns in human tissues and hematopoietic cell subsets J Virol. 2009;83:9474-9485.
doi: 10.1128/JVI.01089-09.

38. Refsland EW, Stenglein MD, Shindo K, et al. Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction. Nucl Acids Res. 2010;38:4274 -4284.
doi: 10.1093/nar/gkq174.

39. Blanc V, Davidson NO. C-to-U RNA Editing: Mechanisms leading to genetic diversity. J. Biol. Chem. 2003;278:1395-1398.
doi: 10.1074/jbc.R200024200.
40. Blanc V, Davidson NO. APOBEC-1-mediated RNA editing. Wiley Interdiscip Rev Syst Biol Med. 2010;2:594-602. doi: 10.1002/wsbm.82.

41. Nishikura K, Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem. 2010;79:321-349.

42. Samuel CE. Adenosine deaminases acting on RNA (ADARs) are both antiviral and proviral. Virology. 2011;411:180-193. doi: 10.1016/j.virol.2010.12.004.

43. Slotkin W, Nishikura K. Adenosine-to-inosine RNA editing and human disease Genome Medicine. 2013;5:105. http://genomemedicine.com/content/5/11/105.

44. Agranat L, Sperling J, Sperling R. A novel tissue-specific alternatively spliced form of the A-to-I RNA editing enzyme ADAR2. RNA Biol. 2010;7:253-262. PMCID: PMC3062093.

45. Picardi EC, Manzari, C, Mastropasqua F, et al. Profiling RNA editing in human tissues: towards the inosinome Atlas. Scientific Reports. 2015;5:14941.
doi: 10.1038/srep14941.

46. Wu DD, Ye L-Q, Li Y, et al. Integrative analyses of RNA editing, alternative splicing, and expression of young genes in human brain transcriptome by deep RNA sequencing. J Mol Cell Biol. 2015;7:1–12.
doi: 10.1093/jmcb/mjv043.

47. O'Connell MA, Mannion NM, Keegan LP. The epitranscriptome and innate immunit. PLoS Genet. 2015;11 :e1005687.
doi: 10.1371/journal.pgen.100568.

48. Paz-Yaacov Levanon NEY, Nevo E, et al. Adenosine-to-inosine RNA editing shapes transcriptome diversity in primates. Proc Natl Acad Sci USA. 2010;107:12174-12179. doi: 10.1073/pnas.1006183107.

49. George CX, Samuel CE. Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible. Proc Natl Acad Sci USA. 1999:96:4621-4626.

50. George CX, Wagner MV, Samuel CE. Expression of interferon-inducible RNA adenosine deaminase ADAR1 during pathogen infection and mouse embryo development involves tissue-selective promoter utilization and alternative splicing. J Biol Chem. 2005;280:15020-15028.
doi: 10.1074/jbc.M500476200.

51. Herbert A, Alfken J, Kim Y-G, et al. A Z-binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase. Proc Natl Acad Sci USA. 1997;94:8421-8426. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC22942/pdf/pq008421.pdf.

52. Herbert A, Rich A. The role of binding domains for dsRNA and Z-DNA in the in vivo editing of minimal substrates by ADAR1. Proc Natl Acad Sci USA. 2001;98:12132-12137.
doi: 10.1073/pnas.211419898.

53. Thomas JM, Beal PA. How do ADARs bind RNA? New protein-RNA structures illuminate substrate recognition by the RNA editing ADARs. Bioessays: News and Reviews in Molec, Cellular and Devel Biol. 2017 Apr;39(4).
doi: 10.1002/bies.201600187.

54. Chen CX, Cho DS, Wang Q, et al. A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. RNA. 2000;6:755-767. http://rnajournal.cshlp.org/content/6/5/755.long.

55. Oakes E, Anderson A, Cohen-Gadol A, et al. Adenosine Deaminase that acts on RNA 3 (ADAR3) binding to glutamate receptor subunit B pre-mRNA inhibits RNA editing in Glioblastoma. J Biol Chem. 2017;292(10):4326-4335.
doi: 10.1074/jbc.M117.779868.

56. Mladenova D, Barry G, Konen LM, et al. Adar3 Is Involved in Learning and Memory in Mice. Front Neurosci. 2018 Apr 13;12:243.
doi: 10.3389/fnins.2018.00243.

57. Lindahl T. Instability and decay of the primary structure of DNA. Nature. 1993;362(6422):709-715.
doi: 10.1038/362709a0.

58. Zheng YC, Lorenzo C, Beal PA, DNA Editing in DNA/RNA hybrids by adenosine deaminases that act on RNA. Nucleic Acids Res. 2017;45:3369-3377.
doi: 10.1093/nar/gkx05.

59. Brambatia A, Zardoniab L, Nardinia E, et al. The dark side of RNA:DNA hybrids. Mutation Research/Reviews in Mutation Research. 2020;784:108300.
doi: 10.1016/j.mrrev.2020.108300.

60. Steele EJ, Lindley RA. ADAR deaminase A-to-I editing of DNA and RNA moieties of RNA:DNA hybrids has implications for the mechanism of Ig somatic hypermutation. DNA Repair. 2017;55:1-6.
doi: 10.1016/j.dnarep.2017.04.004.

61. Longerich S, Meira L, Shah D, et al. Alkyladenine DNA glycosylase (Aag) in somatic hypermutation and class switch recombination. DNA Repair. 2007;6:1764-1773. doi: 10.1016/j.dnarep.2007.06.012.

62. Mamrot J, Balachandran S, Steele EJ, et al. Molecular model linking Th2 polarized M2 tumour‐associated macrophages with deaminase‐mediated cancer progression mutation signatures. Scand J of Immunol. 2019;89(5):e12760. doi: 10.1111/sji.12760.

63. Gallo A, Galardi S. A-to-I RNA editing and cancer: from pathology to basic science. RNA Biol. 2008;5:135-139. PMID: 18758244.

64. Gallo A, Locatelli F. ADARs: allies or enemies? The importance of A-to-I RNA editing in human diseases: from cancer to HIV1. Biol Rev Camb Philos Soc. 2012;87:95-110. doi: 10.1111/j.1469-185X.2011.00186.x.

65. Chan TH, Lin CH, Qi L, et al. 2014. A disrupted RNA editing balance mediated by ADARs (Adenosine Deaminases that act on RNA) in human hepatocellular carcinoma. Hepatology. 2014l63:832 -843.
doi: 10.1136/gutjnl-2012-304037.

66. Chan THM, Qamra A, Tan KT, et al. ADAR-Mediated RNA Editing Predicts Progression and Prognosis of Gastric Cancer. Gastroenterology. 2016;151:637- 650. doi: 10.1053/j.gastro.2016.06.043.

67. Tomasetti C, Vogelstein B, Parmigiani. G. Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumour initiation. Proc Natl Acad Sci USA. 2013;110:1999–2004.
doi: 10.1073/pnas.1221068110.

68. Bass BL. RNA editing by adenosine deaminases that act on RNA. Ann Rev Biochem. 2002;71:817-846. doi: 10.1146/annurev.biochem.71.110601.135501.

69. Ramaswami G, Li JB. RADAR: a rigorously annotated database of A-to-I RNA editing. Nucleic Acids Res. 2014;42:D109–113.
doi: 10.1093/nar/gkt996.

70. Jablonka E. The evolutionary implications of epigenetic inheritance. Interface Focus. 2017;7(5):20160135.
doi: 10.1098/rsfs.2016.0135.

71. Lindley RA. How Evolution Occurs: Was Lamarck Also Right? EdgeScience. 2011a;8:6-9.

72. Lindley RA. Born to Evolve; How Mutational and Epigenetic Changes Enable Adaptive Evolution. G.I.T Laboratory J. 2011b;1 September:3-4.

73. Lindley RA. A new treaty between disease and evolution - are deaminases the “universal mutators” responsible for our own evolution? EdgeScience. December 2018;36:16-20.

74. Scourzic L, Mouly E, Bernard OA. TET proteins and the control of Cytosine demethylation. Cancer Genome Med. 2015;7(1):9. doi: 10.1186/s13073-015-0134-6.
75. Guo JU1, Su Y, Zhong C, et al. Hydroxylation of 5-MethylCytosine by TET2 Promotes Active DNA Demethylation in the Adult Brain. Cell. 2011;145(3):423-434. doi: 10.1016/j.cell.2011.03.022.
76. Cerami E, Gao J, Dogrusoz U, et al.. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discovery. 2012;2(5):401-404.
doi: 10.1158/2159-8290.CD-12-0326.

77. Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science Signaling.2013; 6(269):l1.
doi: 10.1126/scisignal.2004088.

78. Lindley RA, Humbert, Larmer PC, et al. Association between Targeted Somatic Mutation (TSM) signatures and HGS-OvCa progression. Cancer Med. 2016;5:2629-2640.
doi: 10.1002/cam4.825.

79. Gourraud PA, Karaouni A, Woo JM, et al. APOBEC3H haplotypes and HIV-1 pro-viral vif DNA sequence diversity in early untreated human immunodeficiency virus-1 infection. Hum. Immunol. 2011;72:207–212.
doi: 10.1016/j.humimm.2010.12.008.

80. Rathmore A, Carpenter MA, Demir O, et al The local dinucleotide preference of APOBEC3G can be altered from 5'-CC to 5'-TC by a single amino acid substitution. J Mol Biol. 2013;425(22):4442-54.
doi: 10.1016/j.jmb.2013.07.040.

81. Lindley RA. The importance of codon context for understanding the Ig-like somatic hypermutation strand-biased patterns in TP53 mutations in breast cancer. Cancer Genet. 2013;206:222-226.
doi: 10.1016/j.cancergen.2013.05.016.

82. Suspène R, Guetard D, Henry M, et al. Extensive editing of both hepatitis B virus DNA strands by APOBEC3 Cytidine deaminases in vitro and in vivo. Proc of the Natl Acad of Science USA. 2005;102(23):8321–8326.
doi: 10.1073/pnas.0408223102.

83. Vartanian J-P, Henry M, Marchio A, et al. Massive APOBEC3 editing of hepatitis B viral DNA in cirrhosis. PLoS Pathogens. 2010;6:e1000928.
doi: 10.1371/journal.ppat.1000928.

84. Lindley RA, Steele EJ. ADAR and APOBEC editing signatures in viral RNA during acute-phase innate immune responses of the host-parasite relationship to Flaviviruses. Research Reports. 2018;2:e1-e22.
doi: 10.9777/rr.2018.10325.

85. Lindley RA, Hall NA. APOBEC and ADAR deaminases may cause many single nucleotide polymorphisms curated in the OMIM database, Mutat Res Fund Mol Mech Mutagen. 2018;810:33-38.
doi: 10.1016/j.mrfmmm.2018.03.008.

86. Dieci MV, Smutná V, Scott V, et al. 2016 Whole exome sequencing of rare aggressive breast cancer histologies. Breast cancer research and treatment. 2016;156:21-32. doi: 10.1007/s10549-016-3718-y.

87. Li M, Sun Q, Wang X. Transcriptional landscape of human cancers. Oncotarget. 2017;8:34534-34551.
doi: 10.18632/oncotarget.15837.

88. Kjällquist U, Erlandsson R, Tobin NP, et al. Exome sequencing of primary breast cancers with paired metastatic lesions reveals metastasis-enriched mutations in the A-kinase anchoring protein family (AKAPs). BMC cancer. 2018;18:174. doi:1 0.1186/s12885-018-4021-6.

89. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol. 2014;232:513–545.

90. Murphy K, Weaver C, Mowat A, et al. Janeway's Immunobiology 9th Edition, G.S. Garland. Science, Taylor & Francis Group, New York and London. 2017.

91. Gonzalez MC, Suspène R, Henry M, et al. Human APOBEC1 Cytidine deaminase edits HBV DNA. Retrovirology. 2009;6:96. doi: 10.1186/1742-4690-6-96.

92. Roberts SA, Gordenin DA. Hypermutation in human cancer genomes: footprints and mechanisms. Nature Reviews Cancer. 2014;14:786-800. doi: 10.1038/nrc3816.

93. Steele EJ, Lindley RA. Somatic mutation patterns in non-lymphoid cancers resemble the strand biased somatic hypermutation spectra of antibody genes. DNA Repair. 2010;9:600-603. doi: 10.1016/j.dnarep.2010.03.007.

94. Steele EJ. Somatic hypermutation in immunity and cancer: Critical analysis of strand-biased and codon-context mutation signatures. DNA Repair. 2016;45:1-24. doi: 10.1016/j.dnarep.2016.07.001.

95. Storici F, Bebenek K, Kunkel TA, et al. RNA-templated DNA repair. Nature. 2007;447:338-341.
doi: 10.1038/nature05720.

96. Luan DD, Korman MH, Jakubczak JL, et al. Reverse transcription of R2B mRNA is primed by a nick at the chromosomal target site; A mechanism for non-LTR retrotransposition. Cell. 1993;72:595-605. PMID: 7679954.

97. Di Noia JM, Neuberger MS. Molecular mechanisms of somatic hypermutation, Annu Rev Biochem. 2007;76:1-22. doi: 10.1146/annurev.biochem.76.061705.090740.

98. Chan K, Gordenein DA. Clusters of multiple mutations: Incidence and molecular mechanisms Annu Rev Genet. 2015;49:243-267. doi: 10.1146/annurev-genet-112414-054714.

99. Morgan HD, Dean W, Coker HA, et al. Activation-induced cytidine deaminase deaminates 5-Methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J Biol Chem. 2004:279:52353-52360.
doi: 10.1074/jbc.M407695200.

100. Nabel CS, Manning SA, Kohli RM. The curious chemical biology of cytosine: deamination, methylation and oxidation as modulators of genomic potential. ACS Chem Biol. 2012;7:20-30. doi: 10.1021/cb2002895.

101. Teng G, Papavasiliou FN. Immunoglobulin somatic hypermutation. Annual Rev Genet. 2007;41:107-120. doi: 10.1146/annurev.genet.41.110306.130340.

102. Petersen-Mahrt SK, Harris RS, Neuberger MS. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification, Nature. 2002;418:99-104. doi: 10.1038/nature00862.

103. Di Noia J, Neuberger MS. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase, Nature. 2002;419:43-48. doi: 10.1038/nature00981.

104. Harris RS, Petersen-Mahrt SK, Neuberger MS. RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. Mol Cell. 2002;10:1247-1253. doi: 10.1016/S1097-2765(02)00742-6.

105. Harris RS, Bishop KN, Sheehy AM, et al. DNA deamination mediates innate immunity to retroviral infection, Cell. 2003;113:803–809. doi: 10.1016/S0092-8674(03)00423-9.

106. Muramatsu M, Sankaranandi VS, Anant S, et al. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal centre B Cells. J Biol Chem. 1999;274:18470-18476. http://www.jbc.org/content/274/26/18470.long.
107. Lindley RA, Steele EJ. Critical analysis of strand-biased somatic mutation signatures in TP53 versus Ig genes, in genome wide data and the etiology of cancer ISRN Genomics. Vol 2013 Article ID 921418, 18 pages. https://www.hindawi.com/journals/isrn/2013/921418/

108. Zeng X, Winter DB, Kasmer C. et al. DNA polymerase-eta as an A-T mutator in somatic hypermutation of immunoglobulin variable genes, Nat Immunol. 2001;2:537-541. doi: 10.1038/88740.

109. Delbos F, Aoufouchi S, Faili A, et al. DNA polymerase-eta is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse, J Exp Med. 2007;204:17-23 doi: 10.1084/jem.20062131.

110. Franklin A, Milburn PJ, Blanden RV, et al. Human DNA polymerase-eta an A-T mutator in somatic hypermutation of rearranged immunoglobulin genes, is a reverse transcriptase. Immunol Cell Biol. 2004;82:219-225. doi: 10.1046/j.0818-9641.2004.01221.x.

111. Wilson TM, Vaisman A, Martomo SA, et al. MSH2-MSH6 stimulates DNA polymerase eta, suggesting a role for A:T mutations in antibody genes, J Exp Med. 2005;201:637-645.
doi: 10.1084/jem.20042066.

112. Su Y, Egli M, Guengerich FP. Human DNA polymerase η accommodates RNA for strand extension. J Biol Chem. 2017;292:18044-18051.
doi: 10.1074/jbc.M117.809723.

113. Su Y, Ghodke PP, Egli M, et al. Human DNA polymerase η has reverse transcriptase activity in cellular environments. J Biol Chem. 2019;294:6073–6081.
doi: 10.1074/jbc.RA119.007925.

114. Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science. 2013;339:1546-1558. doi: 10.1126/science.1235122.

115. Mooney RA, Artsinovitch I, Landick R. Information processing by RNA polymerase: recognition of regulatory signals during RNA chain elongation. J Bact. 1998;180: 3265-3275.

116. Moore MJ, Proudfoot NJ. Pre-mRNA processing reaches back to transcription and ahead to translation. Cell. 2009;136:688-700.
doi: 10.1016/j.cell.2009.02.001.

117. Sohail A, Klapacz J, Samaranayake M, et al. Human activation-induced cytidine deaminase causes transcription dependent, strand-biased C to U deaminations. Nucl Acids Res. 2003;31:2990-2994. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC162340/.

118. Basu U, Meng FL, Keim C, et al. The RNA Exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell. 2011;144:353-363. D
oi: 10.1016/j.cell.2011.01.001.

119. Kuraoka I, Endou M, Yamaguchi Y. Effects of endogenous DNA base lesions on transcription elongation by mammalian RNA polymerase II. J Biol Chem. 2003;278:7294-7299.
doi: 10.1074/jbc.M208102200.

120. Paul MS, Bass BL. Inosine exists in mRNA at tissue-specific levels and is most abundant in brain mRNA. EMBO J. 1998;17:1120=1127.
doi: 10.1093/emboj/17.4.1120

121. Steele EJ, Lindley RA, Wen J, Weiler GF. Computational analyses show A-to-G mutations correlate with nascent mRNA hairpins at somatic hypermutation hotspots. DNA Repair. 2006;5:1346-1363. doi: 10.1016/j.dnarep.2006.06.002.

122. Samuel CE. Adenosine deaminase acting on RNA (ADAR1), a suppressor of double-stranded RNA-triggered innate immune responses. J Biol Chem. 2019;294(5):1710‐1720.
doi: 10.1074/jbc.TM118.004166.

123. Brody Y, Neufeld N, Bieberstein N, et al. The in vivo kinetics of RNA Polymerase II elongation during co-transcriptional splicing. PLoS Biol. 2011;9(1):e1000573. doi: 10.1371/journal.pbio.1000573.

124. Veloso A, Kirkconnell KS, Magnuson B, et al. Rate of elongation by RNA polymerase II is associated with specific gene features and epigenetic modifications. Genome Res. 2014;24:896-905.
doi: 10.1101/gr.171405.113.

125. Dye MJ, Gromak N, Proudfoot NJ. Exon tethering in transcription by RNA polymerase II. Mol. Cell. 2006;21:849–859. doi: 10.1016/j.molcel.2006.01.032.

126. Chang YF, Imam JS, Wilkinson MF. The nonsense-mediated decay RNA surveillance pathway. Annu Rev of Biochem. 2007;76:51-74.

127. Iborra FJ, Pombo A, Jackson DA, Cook PR. Active RNA polymerases are localised within discrete transcription’factories’ in human nuclei. J Cell Sci. 1996:109:1427-1436.

128. Eskiw CH, Rapp A., Carter DRF et al. RNA polymerase II activity is
located on the surface of protein-rich transcription factories. J Cell Sci. 121 (2008) 1999-2007.
doi: 10.1242/jcs.027250.

129. Osborne CS, Chakalova L, Mitchell JA, et al. Myc dynamically and preferentially relocates to a transcription factory occupied by Igh. PLoS Biol. 2007;5(8):e192.
doi: 10.1371/journal.pbio.0050192.

130. Cook PR. A model for all genomes: the role of transcription factories. J Mol Biol. 2010;395:1-10.
doi: 10.1016/j.jmb.2009.10.031.