AID/APOBEC–dependent somatic hypermutation and DNA rearrangements of immunoglobulin and non-immunoglobulin genes
Keywords:
AID/APOBEC family of deaminases, DNA editing, Ig genes somatic hypermutation, Ig class switching recombination gene, AID/APOBEC off-targets, double-stranded DNA breaks, superenhancers, transcription factors, histone epigenetic modifications, non-coding RNA.Abstract
Editing Ig genes by activation induced deaminase (AID) initiates the antibody diversification process in B lymphocytes.In mammalian B cells, this process includes somatic hypermutation (SHM) and class switch recombination (CSR).The activity of AID is largely confined to switch regions and Ig variable regions but now it is well established that AID/APOBEC-dependent damage and double DNA breaks leading to genome rearrangements and somatic mutagenesis are pervasive throughout the B cell genome. In this review, we focus on the molecular mechanisms that guide AID/APOBEC mutator to physiological and non-physiological targets. Epigenetic modifications, such as histone post-translational modifications and DNA methylation, cis-elements of DNA and the transcription factors that bind to it, which form regulatory clusters and superenhancers, synthesis of non-coding RNA and features of the transcription mode are involved in targeting of AID/APOBEC deaminases to Ig and non-Ig locus. However, not one of the studied factors is specific for the AID target loci. Thus, to date, there is insufficient clarity on the question of what determines the genetically programmed activity of AID in Ig loci and the genetically unprogrammed activity of AID/APOBEC family deaminases in non-Ig loci. The study of AID/APOBEC-dependent somatic hypermutation and rearrangements of Ig and non-Ig locus have both fundamental biological and applied medical significance. The fundamental significance is that the mechanisms of genetic rearrangements in somatic cells can provide a key to understanding the patterns of evolutionary variability of living organisms. The applied value is that based on the data obtained on the genomic instability of non-Ig loci, methods can be developed that suppress the instability of the genome during carcinogenesis and slow down the formation of chemotherapy resistant variants.
References
Stavrou S., Ross S. R. APOBEC3 proteins in viral immunity. 2015. J Immunol. V. 195. P. 4565–4570.
Refsland E. W., Harris R. S. The APOBEC3 family of retroelement restriction factors. Curr Top Microbiol Immunol. 2013. V.371. P.1–27.
Duggal N. K, Emerman M. Evolutionary conflicts between viruses and restriction factors shape immunity. Nat Rev Immunol. 2012. V.12. P. 687–695.
Casellas R., Basu U., Yewdell W.T. [et. al.] Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity. Nat Rev Immunol. 2016. V.16. P. 164–240.
Liu M. C., Liao W. Y., Buckley K. M. [et. al.] AID/APOBEC-like cytidine deaminases are ancient innate immune mediators in invertebrates. Nat Commun. 2018. V.16, P. 1948.
Boehm T. [et al.] VLR-based adaptive immunity. Annu Rev Immunol. 2012. V.30. P. 203–220.
Krishnan A., Iyer L. M., Holland S. J. [et. al.] Diversification of AID/APOBEC-like deaminases in metazoa: multiplicity of clades and widespread roles in immunity. Proc Natl Acad Sci USA. 2018. V.115. P. E3201–E3210.
Zhang D., Iyer L. M., Aravind L. A novel immunity system for bacterial nucleic acid degrading toxins and its recruitment in various eukaryotic and DNA viral systems. Nucleic Acids Res. 2011. V.39. P. 4532–4552.
Iyer L. M., Zhang D., Rogozin I. B., Aravind L. Evolution of the deaminase fold and multiple origins of eukaryotic editing and mutagenic nucleic acid deaminases from bacterial toxin systems. Nucleic Acids Res. 2011. V.39. P. 9473–9497.
Metzger M. J. [et al.] Widespread transmission of independent cancer lineages within multiple bivalve species. Nature. 2016. V.534. P. 705–709.
Hanington P. C. [et al.] Role for a somatically diversified lectin in resistance of an invertebrate to parasite infection. Proc Natl Acad Sci USA. 2010. V.107. P. 21087–21092.
Rouaud P., Vincent-Fabert C., Saintamand A., Fiancette R. [et al.] The IgH 3’ regulatory region controls somatic hypermutation in germinal center B cells. J. Exp. Med. 2013. V.210. P. 1501–1507.
Saintamand A., Rouaud P., Saad F., Rios G. [et al.] Elucidation of IgH 3’ region regulatory role during class switch recombination via germline deletion. Nat. Commun. 2015. V.6. P. 7084.
Buerstedde J. M., Alinikula J., Arakawa H. [et al.] Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. PLoS Biol. 2014. V.12. P. e1001831.
Delgado-Benito V., Rosen D. B., Wang Q. [et al.] The Chromatin Reader ZMYND8 Regulates Igh Enhancers to Promote Immunoglobulin Class Switch Recombination. Mol Cell. 2018., V.72. P. 636–649.e8.
Hauser J., Grundström C., Kumar R. [et al.] Regulated localization of an AID complex with E2A, PAX5 and IRF4 at the Igh locus. Mol Immunol. 2016. V.80. P. 78–90.
Sheppard E. C., Morrish R. B., Dillon M. J. [et al.] Epigenomic Modifications Mediating Antibody Maturation. Front Immunol. 2018. V.26. P. 9–355.
Wang Q., Oliveira T., Jankovic M. [et al.] Epigenetic targeting of activation-induced cytidine deaminase. Proc Natl Acad Sci U S A. 2014. V. 111. P. 18667-18759.
Pavri R. [et al.] Activation-induced cytidine deaminase targets DNA at sites of RNA polymerase II stalling by interaction with Spt5. Cell. 2010. V. 143. P. 122–133.
Yamaguchi Y., Takagi T., Wada T. [et al.] NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell. 1999. V. 97. P. 41–51.
Rahl P. B., Lin C. Y., Seila A. C. [et al.] c-Myc Regulates Transcriptional Pause Release. Cell. 2010. V.141. P. 432–445.
Yamane A., Resch W., Kuo N. [et al.] Deep-sequencing identification of the genomic targets of the cytidine deaminase AID and its cofactor RPA in B lymphocytes. Nat Immunol. 2011. V.12. P. 62–69.
Adelman K., Lis.J. T. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat Rev Genet. 2012. V.13. P. 720–751.
Chaudhuri J., Khuong C., Alt F. W. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature. 2004. V.430. P. 992–998.
Pefanis E. [et al.] Noncoding RNA transcription targets AID to divergently transcribed loci in B cells. Nature. 2014. V.514. P. 389–393.
Core L. J. [et al.] Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nat. Genet. 2014. V.46. P. 1311–1320.
Chen J., Cai Z., Bai M. [et al.] The RNA-binding protein ROD1/PTBP3 cotranscriptionally defines AID-loading sites to mediate antibody class switch in mammalian genomes. Cell Research. 2018. V.28. P. 981–995.
Zheng S., Vuong B. Q., Vaidyanathan B. [et al.] Non-coding RNA generated following lariat-debranching mediates targeting of AID to DNA. Cell. 2015. V.161. P. 762–773.
Chandra V., Bortnick A., Murre C. AID targeting: old mysteries and new challenges. Trends Immunol. 2015. V.36. P. 527–562.
Pasqualucci L. [et al.] BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad Sci USA. 1998. V.95. P. 11816–11821.
Liu M. [et al.] Two levels of protection for the B cell genome during somatic hypermutation. Nature. 2008. V.451. P. 841–845.
Staszewski O. [et al.] Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells. Mol. Cell. 2011. V.41.
P. 232–242.
Qian J. [et al.] B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity. Cell. 2014. V.159. P. 1524–1537.
Dominguez P. M., Teater M., Chambwe N. [et al.] Methylation Dynamics of Germinal Center B Cells Are Mediated by AID. Cell Rep. 2015. V. 29, P. 2086–1284.
Álvarez-Prado Á. F., Pérez-Durán P., Pérez-García A. [et al.] A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets. J Exp Med. 2018. V. 215, P. 761–771.
Hoang P. H., Dobbins S. E., Cornish A. J. [et al.] Whole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms. Leukemia. 2018. V.32. P. 2459–2470.
Li Z., Abraham B. J., Berezovskaya A. [et al.] APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL. Leukemia. 2017. V.31. P. 2057–2064.
Alexandrov L. B. [et al.] Signatures of mutational processes in human cancer. Nature. 2013. V.500. P. 415–421.
Stephens P. J. [et al.] Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011. V.144. P. 27–40.
Basu U. [et al.] The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell. 2011. V.144. P. 353–363.
Beekman R., Chapaprieta V., Russiñol N. [et al.] The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia. Nat Med. 2018. V. 24. P. 868–880.
Rogozin I. B., Lada A. G., Goncearenco A. [et al.] Activation induced deaminase mutational signature overlaps with CpG methylation sites in follicular lymphoma and other cancers. Sci Rep. 2016. V. 7. P. 38133.
Rogozin I. B., Roche-Lima A., Lada A. G., Belinky F. [et al.] Nucleotide Weight Matrices Reveal Ubiquitous Mutational Footprints of AID/APOBEC Deaminases in Human Cancer Genomes. Cancers (Basel). 2019. V. 12, pii: E211.
El Kadi N., Wang L., Davis A. [et al.] The EGFR T790M Mutation Is Acquired through AICDA-Mediated Deamination of 5-Methylcytosine following TKI Treatment in Lung Cancer. Cancer Res. 2018. V. 15, P. 6728–6735.
Popp C., Dean W., Feng S. [et al.] Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature. 2010. V.463. P. 1101–1105.
Gibcus J. H., Dekker J. The hierarchy of the 3D genome. Mol Cell. 2013. V.49. P. 773–782.
Meng F. L., Du Z., Federation A. [et al.] Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell. 2014. V. 159, P. 1538–1586.
Lu Z., Pannunzio N. R., Greisman H. A. [et al.] Convergent BCL6 and lncRNA promoters demarcate the major breakpoint region for BCL6 translocations. Blood. 2015. V.126. P. 1730–1731.
Puc J., Aggarwal A. K., Rosenfeld M. G. Physiological functions of programmed DNA breaks in signal-induced transcription. Nat Rev Mol Cell Biol. 2017. V. 18. P. 471–476.
Ju B. G., Lunyak V. V., Perissi V. [et al.] A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science. 2006. N 312. P.1798–1802.
Madabhushi R. [et al.] Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes. Cell. 2015. V.161. P. 1592–1605.
Fernando P., Megeney L. A. Is caspase-dependent apoptosis only cell differentiation taken to the extreme? FASEB J. 2007. V.21. P. 8–17.
Larsen B. D. [et al.] Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks. Proc Natl Acad Sci U S A. 2010. V.107. P. 4230–4235.
Puc J., Kozbial P., Li W. [et al.] Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell. 2015. V.160. P. 367–380.
Perillo B., Ombra M. N., Bertoni A. [et al.] DNA oxidation as triggered by H3K9me2 demethylation drives estrogeninduced gene expression. Science. 2008. V. 319. P. 202–206.
Periyasamy M., Patel H., Lai C. F. [et al.] APOBEC3B-mediated cytidine deamination is required for estrogen receptor action in breast cancer. Cell Rep. 2015. V. 13. P. 108–129.
Deroo B. J., Korach K. S. Estrogen receptors and human disease. J Clin Invest. 2006. V.116. P. 561–570.
Yager J. D., Davidson N. E. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006. V. 354. P. 270–352.
Yang J., Wei X., Tufan T. [et al.] Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer. Genome Biol. 2018. V.19. P. 190.
Lin C., Yang L, Tanasa B. [et al.] Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell. 2009. V.139. P. 1069–1083.
Elliott K., Boström M., Filges S. [et al.] Elevated pyrimidine dimer formation at distinct genomic bases underlies promoter mutation hotspots in UV-exposed cancers. PLoS Genet. 2018. V. 14. P. e1007849.
Mao P., Brown A. J., Esaki S. [et al.] ETS transcription factors induce a unique UV damage signature that drives recurrent mutagenesis in melanoma. Nat Commun. 2018. V.9. P. 26.
Dorsett Y. [et al.] MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. Immunity. 2008. V. 28. P. 630–638.
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