Contribution of cytosine desaminases of AID/APOBEC family to carcinogenesis

  • Irina Zotova Vavilov Institute of General Genetics Russian Academy of Sciences, Saint Petersburg Branch, Universitetskaya nab., 7–9, Saint Petersburg, 199034, Russian Federation; Department of Genetics and Biotechnology, Faculty of Biology, Saint Petersburg State University, Universitetskaya nab., 7–9, Saint Petersburg, 199034, Russian Federation
  • Elena Stepchenkova Vavilov Institute of General Genetics Russian Academy of Sciences, Saint Petersburg Branch, Universitetskaya nab., 7–9, Saint Petersburg, 199034, Russian Federation; Department of Genetics and Biotechnology, Faculty of Biology, Saint Petersburg State University, Universitetskaya nab., 7–9, Saint Petersburg, 199034, Russian Federation
  • Youri Pavlov Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Departments of Microbiology and Pathology; Biochemistry and Molecular Biology; Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA


Cytosine deaminases of the AID/APOBEC family have a weighty influence on human health. These enzymes are part of the innate and humoral immunity; they participate in lipid metabolism and muscle development, protect cells from viruses and regulate retrotransposition. If the activity of AID/APOBEC deaminases is misregulated, they can become “weapons of mass destruction,” causing deaminations in unprotected single-stranded DNA regions leading to genome-wide mutagenesis. Ultimately, mutations contribute to cell malignancy and rapid evolution of cancer cells, helping them to evade the organism’s defense. Also, hypermutable tumor cells develop resistance to anti-cancer drugs. Here we overview current understanding of the structure, functions, and regulation of AID/APOBEC cytosine deaminases in connection to carcinogenesis.


Cytosine deaminases AID/APOBEC, DNA damage, mutation, cancer


Download data is not yet available.


Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A., Behjati, S., Biankin, A. V., Bignell, G. R., Bolli, N., Borg, A., Borresen-Dale, A. L., et al. 2013. Signatures of mutational processes in human cancer. Nature 500(7463):415–421.

Alexandrov, L. B. and Stratton, M. R. 2014. Mutational signatures: the patterns of somatic mutations hidden in cancer genomes. Current Opinion in Genetics & Development 24:52–60.

An, P., Johnson, R., Phair, J., Kirk, G. D., Yu, X., Donfield, S., Buchbinder, S., Goedert, J. J., and Winkler, C. A. 2009. APOBEC3B deletion and risk of HIV-1 acquisition. The Journal of Infectious Diseases 200(7):1054–1058.

Bailey, M. H., Tokheim, C., Porta-Pardo, E., Sengupta, S., Bertrand, D., Weerasinghe, A., Colaprico, A., Wendl, M. C., Kim, J., Reardon, B., et al. 2018. Comprehensive characterization of cancer driver genes and mutations. Cell 173(2):371–385.e318.

Beale, R. C., Petersen-Mahrt, S. K., Watt, I. N., Harris, R. S., Rada, C., and Neuberger, M. S. 2004. Comparison of the differential context-dependence of DNA deamination by APOBEC enzymes: correlation with mutation spectra in vivo. Journal of Molecular Biology 337(3):585–596.

Bhagwat, A. S., Hao, W., Townes, J. P., Lee, H., Tang, H., and Foster, P. L. 2016. Strand-biased cytosine deamination at the replication fork causes cytosine to thymine mutations in Escherichia coli. Proceedings of the National Academy of Sciences of the USA 113(8):2176–2181.

Bishop, K. N., Verma, M., Kim, E., Wolinsky, S. M., and Malim, M. H. 2008. APOBEC3G inhibits elongation of HIV-1 reverse transcripts. PLoS Pathogens 4(12):e1000231.

Bogerd, H. P., Wiegand, H. L., Hulme, A. E., Garcia-Perez, J. L., O’Shea, K. S., Moran, J. V., and Cullen, B. R. 2006. Cellular inhibitors of long interspersed element 1 and Alu retrotransposition. Proceedings of the National Academy of Sciences of the USA 103(23):8780–8785.

Bonvin, M., Achermann, F., Greeve, I., Stroka, D., Keogh, A., Inderbitzin, D., Candinas, D., Sommer, P., Wain-Hobson, S., Vartanian, J.-P., and Greeve, J. 2006. Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication. Hepatology 43(6):1364–74.

Bransteitter, R., Pham, P., Scharff, M. D., and Goodman, M. F. 2003. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNAse. Proceedings of the National Academy of Sciences of the USA 100(7):4102–4107.

Burns, M. B., Lackey, L., Carpenter, M. A., Rathore, A., Land, A. M., Leonard, B., Refsland, E. W., Kotandeniya, D., Tretyakova, N., Nikas, J. B., Yee, D., Temiz, N. A., Donohue, D. E., McDougle, R. M., Brown, W. L., Law, E. K., and Harris, R. S. 2013. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494(7437):366–370.

Burns, M. B., Temiz, N. A., and Harris, R. S. 2013. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nature Genetics 45(9):977–983.

Canugovi, C., Samaranayake, M., and Bhagwat, A. S. 2009. Transcriptional pausing and stalling causes multiple clustered mutations by human activation-induced deaminase. The FASEB Journal 23(1):34–44.

Cao, W. and Wu, W. 2017 Apolipoprotein B mRNA Editing Enzyme, Catalytic Polypeptide-Like Gene Expression, RNA Editing, and MicroRNAs Regulation. MicroRNA and Cancer. Methods in Molecular Biology, vol. 1699. Humana Press, New York, NY.

Casali, P., Pal, Z., Xu, Z., and Zan, H. 2006. DNA repair in antibody somatic hypermutation. Trends in Immunology 27(7):313–21.

Casellas, R., Basu, U., Yewdell W. T., Chaudhuri, J., Robbiani, D., and Di Noia, J. M. 2016. Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity. Nature Reviews Immunology 16(3):164–176.

Caval, V., Bouzidi, M.S., Suspène, R., Laude, H., Dumargne, M., Bashamboo, A., Krey, T., Vartanian, J., and Wain-Hobson, S. 2015. Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme. Nucleic Acids Research 43(19):9340–9.

Caval, V., Suspene, R., Shapira, M., Vartanian, J., and Wain-Hobson, S. 2014. A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3’UTR enhances chromosomal DNA damage. Nature Communications 5:5129.

Cescon, D. W. and Haibe-Kains, B. 2016. DNA replication stress: a source of APOBEC3B expression in breast cancer. Genome Biology 17:202.

Chaipan, C., Smith, J. L., Hu, W., and Pathak, V. 2013. APOBEC3G restricts HIV-1 to a greater extent than APOBEC3F and APOBEC3DE in human primary CD4 T cells and macrophages. Journal of Virology 87(1):444–453.

Chan, K. and Gordenin, D. A. 2015. Clusters of multiple mutations: incidence and molecular mechanisms. Annual Review of Genetics 49:243–267.

Chan, K., Roberts, S. A., Klimczak, L. J., Sterling, J. F., Saini, N., Malc, E. P., Kim, J., Kwiatkowski, D. J., Fargo, D. C., Mieczkowski, P. A., Getz, G., and Gordenin, D. A. 2015. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nature Genetics 47(9):1067–72.

Chen, H., Lilley, C. E., Yu, Q., Lee, D. V., Chou, J., Narvaiza, I., Landau, N. R., and Weitzman, M. D. 2006. APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons. Current Biology 16(5):480–485.

Chen, S. H., Habib, G., Yang, C. Y., Gu, Z. W., Lee, B. R., Weng, S. A., Silberman, S. R., Cai, S. J., Deslypere, J. P., and Rosseneu, M. 1987. Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. Science 238(4825):363–366.

Choudhary, M., Tamrakar, A., Singh, A. K., Jain, M., Jaiswal, A., and Kodgire, P. 2017. AID Biology: a pathological and clinical perspective. International Reviews of Immunology 37(1):1–20.

Chowdhury, D., Keogh, M-C., Ishii, H., Peterson, C. L., Buratowski, S., and Lieberman, J. 2005. γ-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair. Molecular Cell 20(5):801–809.

Conticello, S. G. 2008. The AID/APOBEC family of nucleic acid mutators. Genome Biology 9(6):229.

Davidson, N. O., Innerarity T. L., Scott, J., Smith, H., Driscoll, D. M., Teng, B., and Chan, L. 1995. Proposed nomenclature for the catalytic subunit of the mammalian apolipoprotein B mRNA editing enzyme: APOBEC-1. RNA 1(1):3.

Di Noia, J. M. and Neuberger, M. S. 2004. Immunoglobulin gene conversion in chicken DT40 cells largely proceeds through an abasic site intermediate generated by excision of the uracil produced by AID-mediated deoxycytidine deamination. European Journal of Immunology 34(2):504–508.

Di Noia, J. M. and Neuberger, M. S. 2007. Molecular mechanisms of antibody somatic hypermutation. Annual Review of Biochemistry 76(1):1–22.

Doehle, B. P., Schafer, A., and Cullen, B. R. 2005. Human APOBEC3B is a potent inhibitor of HIV-1 infectivity and is resistant to HIV-1 Vif. Virology 339(2):281–8.

Fu, Y., Ito, F., Zhang, G., Fernandez, B., Yang, H., and Chen, X. S. 2015. DNA cytosine and methylcytosine deamination by APOBEC3B: enhancing methylcytosine deamination by engineering APOBEC3B. Biochemical Journal 471(Pt 1):25–35.

Gaidano, G., Carbone, A., Pastore, C., Capello, D., Migliazza, A., Gloghini, A., Roncella, S., Ferrarini, M., Saglio, G., and Dalla-Favera, R. 1997. Frequent mutation of the 5' noncoding region of the BCL-6 gene in acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas. Blood 89(10):3755–62.

Gansmo, L., Romundstad, P., Hveem K., Vatten, L., Nik-Zainal, S., Lønning, P.E., and Knappskog, S. 2018. APOBEC3A/B deletion polymorphism and cancer risk. Carcinogenesis 39(2):118–12.

Glaser, A. P., Fantini, D., Wang, Y., Yu, Y., Rimar, K. J., Podojil, J. R., Miller, S. D., and Meeks, J. J. 2018. APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response. Oncotarget 9(4):4537–4548.

Göhler, S., Da Silva Filho, M. I., Johansson, R., Enquist-Olsson, K., Henriksson, R., Hemminki, K., Lenner, P, and Försti, A. 2016. Impact of functional germline variants and a deletion polymorphism in APOBEC3A and APOBEC3B on breast cancer risk and survival in a Swedish study population. Journal of Cancer Research and Clinical Oncology 142(1):273–276.

Goila-Gaur, R., Khan, M. A., Miyagi, E., Kao, S., and Strebel, K. 2007. Targeting APOBEC3A to the viral nucleoprotein complex confers antiviral activity. Retrovirology 4:61.

Green, A. M., Landry, S., Budagyan, K., Avgousti, D. C., Shalhout, S., Bhagwat, A. S., and Weitzman, M. D. 2016. APOBEC3A damages the cellular genome during DNA replication. Cell Cycle 15(7):998–1008.

Hanahan, D. and Weinberg, R. A. 2011. Hallmarks of cancer: the next generation. Cell 144(5):646–74.

Harris, R. S., Bishop, K. N., Sheehy, A. M., Craig, H. M., Petersen-Mahrt, S. K., Watt, I. N., Neuberger, M. S., and Malim, M. H. 2003. DNA Deamination mediates innate immunity to retroviral infection. Cell 113(6):803–809.

Harris, R., Petersen-Mahrt, S., and Neuberger, M. 2002. RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. Molecular Cell 10(5):1247–1253.

Hoopes, J., Cortez, L., Mertz, T., Malc, E. P., Mieczkowski, P. A., and Roberts, S. A. 2016. APOBEC3A and APOBEC3B preferentially deaminate the lagging strand template during DNA replication. Cell Reports 14(6):1273–1282.

Hoopes, J. I., Hughes, A. L., Hobson, L. A., Cortez, L. M., Brown, A. J., and Roberts, S. A. 2017. Avoidance of APOBEC3B-induced mutation by error-free lesion bypass. Nucleic Acids Research 45(9):5243–5254.

Jackson, S. P. and Bartek, J. 2009. The DNA-damage response in human biology and disease. Nature 461(7267):1071–1078.

Jarmuz, A., Chester, A., Bayliss, J., Gisbourne, J., Dunham, I., Scott, J., and Navaratnam, N. 2002. An anthropoid-specific locus of orphan C to U RNA editing enzymes on chromosome 22. Genomics 79(3):285–296.

Jarvis, M. S., Ebrahimi, D., Temiz, N. A., and Harris, R. S. 2018. Mutation signatures including APOBEC in cancer cell lines. JNCI Cancer Spectrum 2(1):pky002.

Jha, P., Sinha, S., Kanchan, K., Qidwai, T., Narang, A., et al. 2012. Deletion of the APOBEC3B gene strongly impacts susceptibility to falciparum malaria. Infections, Genetics and Evolution 12(1):142–148.

Kanu, N., Cerone, M. A., Goh, G., Zalmas, L. P., Bartkova, J., Dietzen, M., et al. 2016. DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer. Genome Biology 17(1):185.

Kazanov, M. D., Roberts, S. A., Polak, P., Stamatoyannopoulos, J., Klimczak, L. J., Gordenin, D. A., and Sunyaev, S. R. 2015. APOBEC-induced cancer mutations are uniquely enriched in early-replicating, gene-dense, and active chromatin regions. Cell Reports 13(6):1103–1109.

Kidd, J., Newman, T. L., Tuzun, E., Kaul, R., and Eichler, E. E. 2007. Population stratification of a common APOBEC gene deletion polymorphism. PLoS Genetics 3(4):e63.

Kinomoto, M., Kanno, T., Shimura, M., Ishizaka, Y., Kojima, A., Kurata, T., Sata, T., and Tokunaga, K. 2007. All APOBEC3 family proteins differentially inhibit LINE-1 retrotransposition. Nucleic Acids Research 35(9):2955–2964.

Krishnan, A., Iyer, L. M., Holland, S. J., Boehm, T., and Aravind, L. 2018. Diversification of AID/APOBEC-like deaminases in metazoa: multiplicity of clades and widespread roles in immunity. Proceedings of the National Academy of Sciences of the USA 115(14):E3201–E3210.

Kumar, R., DiMenna, L. J., Chaudhuri, J., and Evans, T. 2014. Biological function of activation induced cytidine deaminase (AID). Biomed Journal 37(5):269–83.

Lackey, L., Demorest, Z. L., Land, A. M., Hultquist, J. F., Brown, W. L., and Harris, R.S. 2012. APOBEC3B and AID have similar nuclear import mechanisms. Journal of Molecular Biology 419(5):301–314.

Lada, A. G., Dhar, A., Boissy, R, Hirano, M., Rubel, A. A., Rogozin, I. B., and Pavlov, Y. I. 2012. AID/APOBEC cytosine deaminase induces genome-wide kataegis. Biology Direct 7:47.

Lada, A. G., Frahm Krick, C., Kozmin, S. G., Mayorov, V. I., Karpova, T. S., Rogozin, I. B., and Pavlov, Y. I. 2011a. Mutator effects and mutation signatures of editing deaminases produced in bacteria and yeast. Biochemistry (Moscow) 76(1):131–146.

Lada, A. G., Iyer, L. M., Rogozin, I. B., Aravind, L., and Pavlov, Y. I. 2007. Incarnation of classical pro- and eukaryotic mechanisms of mutagenesis in hypermutagenesis and immunity of vertebrates. Russian Journal of Genetics 43(10):1093–1107.

Lada, A. G., Kliver, S. F., Dhar, A., Polev, D. E., Masharsky, A. E., Rogozin, I. B., and Pavlov, Y. I. 2015. Disruption of transcriptional coactivator Sub1 leads to genome-wide re-distribution of clustered mutations induced by APOBEC in active yeast genes. PLoS Genetics 11(5):e1005217ss.

Lada, A. G., Waisertreiger, I. S., Grabow, C. E., Prakash, A., Borgstahl, G. E., Rogozin, I. B., and Pavlov, Y. I. 2011b. Replication protein A (RPA) hampers the processive action of APOBEC3G cytosine deaminase on single-stranded DNA. PLoS One 6(9):e24848.

Lada, A. G., Stepchenkova, E. I, Waisertreiger, I. S., Noskov, V. N., Dhar, A., Eudy, J. D., Boissy, R. J., Hirano M., Rogozin, I. B., and Pavlov, Y. I. 2013. Genome-wide mutation avalanches induced in diploid yeast cells by a base analog or an APOBEC deaminase. PLoS Genetics 9(9):e1003736.

Land, A. M., Law, E. K., Carpenter, M. A., Lackey, L., Brown, W. L., and Harris, R. S. 2013. Endogenous APOBEC3A DNA cytosine deaminase is cytoplasmic and nongenotoxic. Journal of Biological Chemistry 288(24):17253–17260.

Landry, S., Narvaiza, I., Linfesty, D. C., and Weitzman, M. D. 2011. APOBEC3A can activate the DNA damage response and cause cell-cycle arrest. EMBO Reports 12(5):444–450.

Law, E. K., Sieuwerts, A. M., LaPara, K., Leonard, B., Starrett, G. J., Molan, A. M., Temiz, N. A., Vogel, R. I., Meijer-van Gelder, M. E., Sweep, F. C., et al. 2016. The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer. Science Advances 2(10):e1601737.

Li, J., Zhao, X., Gilbert, E. R., Li, D., Liu, Y., Wang, Y., Zhu, Q., Wang, Y., Chen, Y., and Tian, K. 2014. APOBEC2 mRNA and protein is predominantly expressed in skeletal and cardiac muscles of chickens. Gene 539(2):263–269.

Liao, W., Hong, S., Chan, B., Rudolph, F. B., Clark, S. C., and Chan, L. 1999. APOBEC-2, a cardiac- and skeletal muscle-specific member of the cytidine deaminase supergene family. Biochemical and Biophysical Research Communications 260(2):398–404.

Loeb, L. A. 2001. A mutator phenotype in cancer. Cancer Research 61:3230–3239.

Loeb, L. A., Springgate, C. F., Battula, N. 1974. Errors in DNA replication as a basis of malignant changes. Cancer Research 34(9):2311–2321.

Mak, C. H., Pham, P., Afif, S. A., and Goodman, M. F. 2013. A mathematical model for scanning and catalysis on single-stranded DNA, illustrated with activation-induced deoxycytidine deaminase. Journal of Biological Chemistry 288(41):29786–29795.

Marino, D., Perković, M., Hain, A., Vasudevan, A., Hofmann, H., Hanschmann, K., Mühlebach, M. D., Schumann, G. G., König, R., Cichutek, K., Häussinger, D., and Münk, C. 2016. APOBEC4 enhances the replication of HIV-1. PloS ONE 11(6):e0155422.

Martincorena, I., Raine, K. M., Gerstung, M., Dawson, K. J., Haase, K., Van Loo, P., Davies, H., Stratton, M. R., and Campbell, P. J. 2017. Universal patterns of selection in cancer and somatic tissues. Cell 171(5):1029–1041.e1021.

Martincorena, I., Roshan, A., Gerstung, M., Ellis, P., Van Loo, P., McLaren, S., Wedge, D. C., Fullam, A., Alexandrov, L. B., Tubio, J. M., et al. 2015. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348(6237):880–886.

Mayorov, V. I., Rogozin, I. B., Adkison, L. R., Frahm, C., Kunkel, T. A., and Pavlov, Y. I. 2005. Expression of human AID in yeast induces mutations in context similar to the context of somatic hypermutation at G-C pairs in immunoglobulin genes. BMC Immunology 6:10.

Middlebrooks, C. D., Banday, A. R., Matsuda, K., et al. 2016. Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC signature mutations in tumors. Nature Genetics 48(11):1330–1338.

Morisawa, T., Marusawa, H., Ueda, Y., Iwai, A., Okazaki, I., Honjo, T., and Chiba, T. 2008. Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression. International Journal of Cancer 123(12):2735–2740.

Muckenfuss, H., Hamdorf, M., Held, U., Perkovic, M., Löwer, J., Cichutek, K., Flory, E., Schumann, G. G., and Münk, C. 2006. APOBEC3 proteins inhibit human LINE-1 retrotransposition. Journal of Biological Chemistry 281:22161–22172.

Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y., and Honjo, T. 2000. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102(5):553–563.

Muramatsu, M., Sankaranand, V. S., Anant, S., Sugai, M., Kinoshita, K., Davidson, N. O., and Honjo, T. 1999. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. Journal of Biological Chemistry 274:18470–18476.

Narvaiza, I., Linfesty, D. C., Greener, B. N., Hakata, Y., Pintel, D. J., Logue, E., Landau, N. R., and Weitzman, M. D. 2009. Deaminase-independent inhibition of parvoviruses by the APOBEC3A cytidine deaminase. PLoS Pathogens 5(5):e1000439.

Neuberger, M. S., Harris, R. S., Di Noia, J., and Petersen-Mahrt, S. K. 2003. Immunity through DNA deamination. Trends in Biochemical Sciences 28(6):305–312.

Nik-Zainal, S., Alexandrov, L., Wedge, D., et al. 2012. Mutational processes molding the genomes of 21 breast cancers. Cell 149(5–10):979–993.

Nik-Zainal, S., Davies, H., Staaf, J., Ramakrishna, M., Glodzik, D., Zou, X., et al. 2016. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534(7605):47–54.

Nik-Zainal, S. and Morganella, S. 2017. Mutational signatures in breast cancer: the problem at the DNA level. Clinical Cancer Research 23(11):2617–2629.

Nik-Zainal, S., Wedge, D., Alexandrov, L., et al. 2014. Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer. Nature Genetics 46(5):487–491.

Nussenzweig, A. and Nussenzweig, M. C. 2010. Origin of chromosomal translocations in lymphoid cancer. Cell 141(1):27–38.

Okazaki, I., Hiai, H., Kakazu, N., Yamada, S., Muramatsu, M., Kinoshita, K., and Honjo, T. 2003. Constitutive expression of AID leads to tumorigenesis. Journal of Experimental Medicine 197(9):1173–1181.

Okazaki, I., Kinoshita, K., Muramatsu, M., Yoshikawa, K., and Honjo, T. 2002. The AID enzyme induces class switch recombination in fibroblasts. Nature 416(6878):340–345.

Okazaki, I., Kotani, A., and Honjo, T. 2007. Role of AID in tumorigenesis. Advances in Immunology 94:245–273.

Okuyama, S., Marusawa, H., Matsumoto, T., Ueda, Y., Matsumoto, Y., Endo, Y., Takai, A., and Chiba, T. 2011. Excessive activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide 2 (APOBEC2) contributes to liver and lung tumorigenesis. International Journal of Cancer 130(6):1294–1301.

Orecchini, E., Frassinelli, L., Galardi, S., Ciafrè, S. A., and Michienzi, A. 2018. Post-transcriptional regulation of LINE-1 retrotransposition by AID/APOBEC and ADAR deaminases. Chromosome Research 25(1–2):45–59.

Papavasiliou, F. N. and Schatz, D. G. 2002. Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity. Cell 109(2):S35–S44.

Pasqualucci, L., Neumeister, P., Goossens, T., Nanjangud, G., Chaganti, R. S. K., Kuppers, R., and Dalla-Favera, R. 2001. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412(6844):341–346.

Pak, V., Heidecker, G., Pathak, V. K., and Derse, D. 2011. The role of amino-terminal sequences in cellular localization and antiviral activity of APOBEC3B. Journal of Virology 85(17):8538–8547.

Periyasamy, M., Patel, H., Lai, C., et al. 2015. APOBEC3B-mediated cytidine deamination is required for estrogen receptor action in breast cancer. Cell Reports 13(1):108–121.

Petersen-Mahrt, S. K., Harris, R. S., and Neuberger, M. S. 2002. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418(6893):99–104.

Pham, P., Bransteitter, R., Petruska, J., and Goodman, M. F. 2003. Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature 424(6944):103–107.

Pham, P., Smolka, M. B., Calabrese, P., Landolph, A., Zhang, K., Zhou, H., and Goodman, M. F. 2008. Impact of phosphorylation and phosphorylation-null mutants on the activity and deamination specificity of activation-induced cytidine deaminase. The Journal of Biological Chemistry 283(25):17428–17439.

Poltoratsky, V., Heacock, M., Kissling, G. E., Prasad, R., and Wilson, S. H. 2010. Mutagenesis dependent upon the combination of activation-induced deaminase expression and a double-strand break. Molecular Immunology 48(1–3):164–170.

Poltoratsky, V. P., Wilson, S. H., Kunkel, T. A., and Pavlov, Y. I. 2004. Recombinogenic phenotype of human activation-induced cytosine deaminase. The Journal of Immunology 172(7):4308–4313.

Powell, L. M., Wallis, S. C., Pease, R. J., Edwards, Y. H., Knott, T. J., and Scott, J. 1987. A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine. Cell 50(6):831–840.

Qian, J., Wang, Q, Dose, M., Pruett, N., Kieffer-Kwon, K., Resch, W., Liang, G., Tang, Z., Mathé, E., Benner, C., Dubois, W., Nelson, S., Vian, L., Oliveira, T. Y., Jankovic, M., Hakim, O., Gazumyan, A., Pavri, R., Awasthi, P., Song, B., Liu, G., Chen, L., Zhu, S., Feigenbaum, L., Staudt, L., Murre, C., Ruan, Y., Robbiani, D. F., Pan-Hammarström, Q., Nussenzweig, M. C., and Casellas, R. 2014. B Cell super-enhancers and regulatory clusters recruit AID tumorigenic activity. Cell 159(7):1524–1537.

Ramiro, A. R., Jankovic, M., Eisenreich, T., Difilippantonio, S., Chen-Kiang, S., Muramatsu, M., Honjo, T., Nussenzweig, A., and Nussenzweig, M. C. 2004. AID is required for c-myc/IgH chromosome translocations in vivo. Cell 118(4):431–438.

Revy, P., Muto, T., Levy, Y., Geissmann, F., Plebani, A., Sanal, O., Catalan, N., Forveille, M., Dufourcq-Labelouse, R., Gennery, A., Tezcan, I., Ersoy, F., Kayserili, H., Ugazio, A. G., Brousse, N., Muramatsu, M., Notarangelo, L. D., Kinoshita, K., Honjo, T., Fischer, A., and Durandy, A. 2000. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102(5):565–575.

Robbiani, D., Bunting, S., Feldhahn, N., Bothmer, A., Camps, J., Deroubaix, S., McBride, K. M., Klein, I. A., Stone, G., Eisenreich, T. R., Ried, T., Nussenzweig, A., and Nussenzweig, M. C. 2009. AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. Molecular Cell 36(4):631–641.

Roberts, S. A. and Gordenin, D. A. 2014. Hypermutation in human cancer genomes: footprints and mechanisms. Nature Reviews Cancer 14(12):786–800.

Roberts, S, Lawrence, M. S., Klimczak, L. J., Grimm, S. A., Fargo, D., Petar Stojanov, P., Kiezun, A., Kryukov, G. V., Carter, S. L., Saksena, G., Harris, S., Shah, R. R., Resnick, M. A., Getz, G., and Gordenin, D. A. 2013. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nature Genetics 45(9):970–976.

Roberts, S., Sterling, J., Thompson, C., Harris, S., Mav, D., Shah, R., Klimczak, L. J., Kryukov, G. V., Malc, E., Mieczkowski, P. A., Resnick, M. A., and Gordenin, D. A. 2012. Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Molecular Cell 46(4):424–435.

Rogozin, I. B., Babenko, V. N., Milanesi, L., and Pavlov, Y. I. 2003. Computational analysis of mutation spectra. Briefings Bioinformatics 4(3):210–227.

Rogozin, I. B., Basu, M. K., Jordan, I. K, Pavlov, Y. I., and Koonin, E. V. 2005. APOBEC4, a new member of the AID/APOBEC family of polynucleotide (deoxy) cytidine deaminases predicted by computational analysis. Cell cycle 4(9):1281–1285.

Rogozin, I. B., Iyer, L. M., Liang, L., Glazko, G. V., Liston, V. G., Pavlov, Y. I., Aravind, L., and Pancer, Z. 2007. Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Nature Immunology 8(6):647–656.

Rogozin, I. B. and Pavlov, Y. I. 2003. Theoretical analysis of mutation hotspots and their DNA sequence context specificity. Mutation Research 544(1):65–85.

Rogozin, I. B. and Pavlov, Y. I. 2006. The cytidine deaminase AID exhibits similar functional properties in yeast and mammals. Molecular Immunology 43(9):1481–1484.

Rogozin, I. B., Pavlov, Y. I., Goncearenco, A., De, S., Lada, A. G., Poliakov, E., Panchenko, A. R., and Cooper, D. N. 2018. Mutational signatures and mutable motifs in cancer genomes. Briefings Bioinformatics 19(6):1–17.

Rogozin, I. B., Roche-Lima, A., Lada, A. G., Belinky, F., Sidorenko, I. A., Glazko, G. V., Babenko, V. N., Cooper, D. N., and Pavlov, Y. I. 2019. Nucleotide weight matrices reveal ubiquitous mutational footprints of AID/APOBEC deaminases in human cancer genomes. Cancers 11(2):211.

Rosenberg, B. R, Hamilton, C. E., Mwangi, M. M., Dewell, S, and Papavasiliou, F. N. 2011. Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA editing targets in transcript 3′ UTRs. Nature Structural & Molecular Biology 18(2):230–236.

Saini, N., Roberts, S. A., Sterling, J. F., Malc, E. P., Mieczkowski, P. A., and Gordenin, D. A. 2017. APOBEC3B cytidine deaminase targets the non-transcribed strand of tRNA genes in yeast. DNA Repair 53:4–14.

Sakofsky, C. J., Roberts, S. A., Malc, E., Mieczkowski, P. A., Resnick, M. A., Gordenin, D. A., and Malkova, A. 2014. Break-induced replication is a source of mutation clusters underlying kataegis. Cell Reports 7(5):1640–1648.

Salter, J. D., Bennett, R. P., and Smith, H. C. 2016. The APOBEC protein family: united by structure, divergent in function. Trends in Biochemical Sciences 41(7):578–594.

Samaranayake, M., Bujnicki, J. M., Carpenter, M., and Bhagwat, A. S. 2006. Evaluation of molecular models for the affinity maturation of antibodies: roles of cytosine deamination by AID and DNA repair. Chemical Reviews 106(2):700–719.

Sato, Y., Ohtsubo, H., Naohiro Nihei, N., Kaneko, T., Sato, Y., Adachi, S., Kondo, S., Nakamura, M., Mizunoya, W., Iida, H., Tatsumi, R., Rada, C., and Yoshizawa, F. 2017. Apobec2 deficiency causes mitochondrial defects and mitophagy in skeletal muscle. The FASEB Journal 32(3):fj.201700493R.

Sato, Y., Probst, H. C., Tatsumi, R., Ikeuchi, Y., Neuberger, M. S., and Rada, C. 2009. Deficiency in APOBEC2 leads to a shift in muscle fiber type, diminished body mass, and myopathy. Journal of Biological Chemistry 285(10):7111–7118.

Schumacher, A. J., Nissley, D. V., and Harris, R. S. 2005. APOBEC3G hypermutates genomic DNA and inhibits Ty1 retrotransposition in yeast. Proceedings of the National Academy of Sciences of the USA 102(28):9854–9859.

Schumann, G. G. 2007. APOBEC3 proteins: major players in intracellular defence against LINE-1-mediated retrotransposition. Biochemical Society Transactions 35(Pt 3):637–642.

Seplyarskiy, V. B., Soldatov, R. A., Popadin, K. Y., Antonarakis, S. E., Bazykin, G. A., and Nikolaev, S. I. 2016. APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication. Genome Research 26(2):174–182.

Sharma, S., Patnaik, S. K., Taggart, R. T., Kannisto, E. D., Enriquez, S. M., Gollnick, P., and Baysal, B. E. 2015. APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages. Nature Communications 6:6881.

Sharma, S., Patnaik, S. K., Kemer, Z., and Baysal, B. E. 2017. Transient overexpression of exogenous APOBEC3A causes C-to-U RNA editing of thousands of genes. RNA Biology 14(5):603–610.

Sheehy, A. M., Gaddis, N. C., Choi, J. D., and Malim, M. H. 2002. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418(6898):646–650.

Shiloh, Y. 2003. ATM and related protein kinases: safeguarding genome integrity. Nature Reviews Cancer 3(3):155–168.

Siriwardena, S. U., Perera, M. L. W., Senevirathne, V., Stewart, J., and Bhagwat, A. S. 2018. A tumor-promoting phorbol ester causes a large increase in APOBEC3A expression and a moderate increase in APOBEC3B expression in a normal human keratinocyte cell line without increasing genomic uracils. Molecular and Cellular Biology 39(1):e00238-18.

Stenglein, M. D. and Harris R. S. 2006. APOBEC3B and APOBEC3F Inhibit L1 Retrotransposition by a DNA Deamination-independent Mechanism. Journal of Biological Chemistry 281:16837–16841.

Stavnezer, J. and Schrader, C. E. 2006. Mismatch repair converts AID-instigated nicks to double-strand breaks for antibody class-switch recombination. Trends in Genetics 22(1):23–28.

Stratton, M. R., Campbell, P. J., and Futreal, P. A. 2009. The cancer genome. Nature 458(7239):719–724.

Suspene, R., Aynauda, M-M., Guétard, D., Henry, M., Eckhoff, G., Marchio, A., Pineau, Dejean, A., Vartanian, J-P., and Wain-Hobson, S. 2011. Somatic hypermutation of human mitochondrial and nuclear DNA by APOBEC3 cytidine deaminases, a pathway for DNA catabolism. Proceedings of the National Academy of Sciences of the USA 108(12):4858–4863.

Suspene, R., Guétard, D., Henry, M., Sommer, P., Wain-Hobson, S., and Vartanian, J-P. 2005. Extensive editing of both hepatitis B virus DNA strands by APOBEC3 cytidine deaminases in vitro and in vivo. Proceedings of the National Academy of Sciences of the USA 102(23):8321–8326.

Suspene, R., Mussil, B., Laude, H., Caval, V., Berry, N., Bouzidi, M. S., Thiers, V., Wain-Hobson, S., and Vartanian, J. 2017. Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage. Nucleic Acids Research 45(6):3231–3241.

Taylor, B., Nik-Zainal, S., Wu, Y. L., Stebbings, L. A., Raine, K., Campbell, P. J., Rada, C., Stratton, M. R., and Neuberger, M. S. 2013. DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis. eLife 2:e00534.

Taylor, B. J., Wu, Y. L., and Rada, C. 2014. Active RNAP pre-initiation sites are highly mutated by cytidine deaminases in yeast, with AID targeting small RNA genes. eLife 3:e03553.

Teng, B., Burant, S., and Davidson, N. 1993. Molecular cloning of an apolipoprotein B messenger RNA editing protein. Science 260(5115):1816–1819.

Vartanian, J. P., Guétard, D., Henry, M., and Wain-Hobson, S. 2008. Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and precancerous lesions. Science 320(5873):230–233.

Walker, B., Wardell, C. P., Murison, A., et al. 2015. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nature Communications 6:6997.

Xiao, X., Yang, H., Arutiunian, V., Fang, Y., Besse, G., Morimoto, C., Zirkle, B., and Chen, X. S. 2017. Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation. Nucleic Acids Research 45(12):7494–7506.

Xuan, D., Li, G., Cai, Q., et al. 2013. APOBEC3 deletion polymorphism is associated with breast cancer risk among women of European ancestry. Carcinogenesis 34(10):2240–2243.

Yamanaka, S., Balestra, M. E., Ferrell, L. D., Fan, J., Arnold, K. S., Taylor, S., Taylor, J. M., and Innerarity, T. L. 1995. Apolipoprotein B mRNA-editing protein induces hepatocellular carcinoma and dysplasia in transgenic animals. Proceedings of the National Academy of Sciences of the USA 92(18):8483–8487.

Yoshikawa, K., Okazaki, I. M., Eto, T., Kinoshita, K., Muramatsu, M., Nagaoka, H., and Honjo, T. 2002. AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296(5575):2033–2036.

Yu, Q., Chen, D., König, R., Mariani, R., Unutmaz, D., and Landau, N. R. 2004. APOBEC3B and APOBEC3C are potent inhibitors of simian immunodeficiency virus replication. Journal of Biological Chemistry 279:53379–53386.

Zan, H. and Casali, P. 2013. Regulation of Aicda expression and AID activity. Autoimmunity 46(2):83–101.

Zhang, T., Cai, J., Chang, J., Yu, D., Wu, C., Yan, T., Zhai, K., Bi, X., Zhao, H., Xu, J., Tan, W., Qu, C., and Lin, D. 2013. Evidence of associations of APOBEC3B gene deletion with susceptibility to persistent HBV infection and hepatocellular carcinoma. Human Molecular Genetics 22(6):1262–1269.

How to Cite
Zotova, I., Stepchenkova, E., & Pavlov, Y. (2019). Contribution of cytosine desaminases of AID/APOBEC family to carcinogenesis. Biological Communications, 64(2), 110–123.
Review communications