Genomes and Genes
immunoglobulin somatic hypermutation
Summary: A programmed mutation process whereby changes are introduced to the nucleotide sequence of immunoglobulin gene DNA during development.
- Revy P, Buck D, Le Deist F, de Villartay J. The repair of DNA damages/modifications during the maturation of the immune system: lessons from human primary immunodeficiency disorders and animal models. Adv Immunol. 2005;87:237-95 pubmed
- Xu Z, Fulop Z, Zhong Y, Evinger A, Zan H, Casali P. DNA lesions and repair in immunoglobulin class switch recombination and somatic hypermutation. Ann N Y Acad Sci. 2005;1050:146-62 pubmed..Aberrant regulation of these events can result in chromosomal breaks and translocations, which are significant steps in B-cell neoplastic transformation. ..
- Yang S, Fugmann S, Schatz D. Control of gene conversion and somatic hypermutation by immunoglobulin promoter and enhancer sequences. J Exp Med. 2006;203:2919-28 pubmed..Our results indicate that cis-acting elements are important for Ig gene diversification, and we propose that targeting specificity is achieved through the combined action of several Ig locus elements that include the promoter. ..
- Di Noia J, Neuberger M. Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem. 2007;76:1-22 pubmed..AID-triggered DNA deamination also underpins immunoglobulin variable (IgV) gene conversion, isotype class switching, and some oncogenic translocations in B cell tumors. ..
- Delbos F, Aoufouchi S, Faili A, Weill J, Reynaud C. 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 pubmed..pol eta thus appears to be the sole contributor of A/T mutations in the normal physiological context. ..
- Bardwell P, Woo C, Wei K, Li Z, Martin A, Sack S, et al. Altered somatic hypermutation and reduced class-switch recombination in exonuclease 1-mutant mice. Nat Immunol. 2004;5:224-9 pubmed..The phenotype of Exo1(-/-) mice and the finding that Exo1 and Mlh1 are physically associated with mutating variable regions support the idea that Exo1 and MMR participate directly in SHM and CSR. ..
- Basu U, Chaudhuri J, Alpert C, Dutt S, Ranganath S, Li G, et al. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature. 2005;438:508-11 pubmed..We conclude that PKA has a critical role in post-translational regulation of AID activity in B cells. ..
- Odegard V, Schatz D. Targeting of somatic hypermutation. Nat Rev Immunol. 2006;6:573-83 pubmed..We review and attempt to reconcile the numerous and sometimes conflicting studies on the targeting of SHM to immunoglobulin loci, and highlight areas that hold promise for further investigation. ..
- Casali P, Pal Z, Xu Z, Zan H. DNA repair in antibody somatic hypermutation. Trends Immunol. 2006;27:313-21 pubmed..Here, we place these concepts in the context of the existing in vivo and in vitro findings, and discuss an integrated mechanistic model of SHM. ..
- Arakawa H, Kudo H, Batrak V, Caldwell R, Rieger M, Ellwart J, et al. Protein evolution by hypermutation and selection in the B cell line DT40. Nucleic Acids Res. 2008;36:e1 pubmed..Artificial evolution in DT40 offers unique advantages and may be easily adapted to other transgenes, if the selection for desirable mutations is feasible. ..
- Wilson T, Vaisman A, Martomo S, Sullivan P, Lan L, Hanaoka F, et al. MSH2-MSH6 stimulates DNA polymerase eta, suggesting a role for A:T mutations in antibody genes. J Exp Med. 2005;201:637-45 pubmed..These observations suggest that the interaction between MSH2-MSH6 and DNA pol eta stimulates synthesis of mutations at bases located downstream of the initial dU lesion, including A:T pairs. ..
- Kothapalli N, Norton D, Fugmann S. Cutting edge: a cis-acting DNA element targets AID-mediated sequence diversification to the chicken Ig light chain gene locus. J Immunol. 2008;180:2019-23 pubmed
- Weill J, Reynaud C. DNA polymerases in adaptive immunity. Nat Rev Immunol. 2008;8:302-12 pubmed publisher..In this Review, we focus on the contribution of a set of DNA polymerases discovered in the past decade to these unique DNA transactions. ..
- Dorsett Y, McBride K, Jankovic M, Gazumyan A, Thai T, Robbiani D, et al. MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. Immunity. 2008;28:630-8 pubmed publisher..A similar but more pronounced translocation phenotype was also found in miR-155-deficient mice. Our experiments indicate that miR-155 can act as a tumor suppressor by reducing potentially oncogenic translocations generated by AID. ..
- Wright B, Schmidt K, Minnick M, Davis N. I. VH gene transcription creates stabilized secondary structures for coordinated mutagenesis during somatic hypermutation. Mol Immunol. 2008;45:3589-99 pubmed publisher..Such a complex of secondary structures may be the source of ssDNA for enzyme-based diversification, which ultimately results in high affinity antibodies. ..
- Faili A, Stary A, Delbos F, Weller S, Aoufouchi S, Sarasin A, et al. A backup role of DNA polymerase kappa in Ig gene hypermutation only takes place in the complete absence of DNA polymerase eta. J Immunol. 2009;182:6353-9 pubmed publisher..Such a dominant behavior may explain the lack of Pol kappa signature in Ig gene mutations of some XPV patients previously described, for whom residual Pol eta activity might exist. ..
- Peron S, Pan Hammarstrom Q, Imai K, Du L, Taubenheim N, Sanal O, et al. A primary immunodeficiency characterized by defective immunoglobulin class switch recombination and impaired DNA repair. J Exp Med. 2007;204:1207-16 pubmed..Overall, these findings suggest that a unique Ig CSR deficiency phenotype could be related to an as-yet-uncharacterized defect in a DNA repair pathway involved in both CSR and SHM events. ..
- Blagodatski A, Batrak V, Schmidl S, Schoetz U, Caldwell R, Arakawa H, et al. A cis-acting diversification activator both necessary and sufficient for AID-mediated hypermutation. PLoS Genet. 2009;5:e1000332 pubmed publisher..The results significantly extend previously reported findings on AID-mediated gene diversification. They show by both deletion and insertion analyses that cis-acting sequences predispose neighboring transcription units to hypermutation. ..
- Li Z, Woo C, Iglesias Ussel M, Ronai D, Scharff M. The generation of antibody diversity through somatic hypermutation and class switch recombination. Genes Dev. 2004;18:1-11 pubmed
- Faili A, Aoufouchi S, Weller S, Vuillier F, Stary A, Sarasin A, et al. DNA polymerase eta is involved in hypermutation occurring during immunoglobulin class switch recombination. J Exp Med. 2004;199:265-70 pubmed
- Beale R, Petersen Mahrt S, Watt I, Harris R, Rada C, Neuberger M. Comparison of the differential context-dependence of DNA deamination by APOBEC enzymes: correlation with mutation spectra in vivo. J Mol Biol. 2004;337:585-96 pubmed
- Ruckerl F, Busse B, Bachl J. Episomal vectors to monitor and induce somatic hypermutation in human Burkitt-Lymphoma cell lines. Mol Immunol. 2006;43:1645-52 pubmed..This observation verifies that overexpression of AID in non hypermutating BL cell lines as well as the expression of endogenous AID in the hypermutating BL cell line Raji can overcome the target restriction of AID. ..
- Longerich S, Tanaka A, Bozek G, Nicolae D, Storb U. The very 5' end and the constant region of Ig genes are spared from somatic mutation because AID does not access these regions. J Exp Med. 2005;202:1443-54 pubmed..Thus, AID does not gain access to the 5' and constant regions of Ig genes. The implications for the role of transcription and Ung in SHM are discussed. ..
- Maizels N. Immunoglobulin gene diversification. Annu Rev Genet. 2005;39:23-46 pubmed..Ubiquitous factors critical for DNA repair carry out all downstream steps, creating mutations and deletions in genomic DNA. This review focuses on the genetic and biochemical mechanisms of diversification of immunoglobulin genes. ..
- Odegard V, Kim S, Anderson S, Shlomchik M, Schatz D. Histone modifications associated with somatic hypermutation. Immunity. 2005;23:101-10 pubmed..These findings indicate that SHM and CSR trigger distinct DNA damage responses and identify a novel histone modification pattern for SHM consisting of H2B(Ser14P) in the absence of gammaH2AX. ..
- Quartier P, Bustamante J, Sanal O, Plebani A, Debre M, Deville A, et al. Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency. Clin Immunol. 2004;110:22-9 pubmed..In conclusion, AID-deficient patients are prone to infections and lymphoid hyperplasia, which may be prevented by early-onset IVIG replacement, but also to autoimmune and inflammatory disorders. ..
- Parsa J, Basit W, Wang C, Gommerman J, Carlyle J, Martin A. AID mutates a non-immunoglobulin transgene independent of chromosomal position. Mol Immunol. 2007;44:567-75 pubmed
- Boursier L, Su W, Spencer J. Analysis of strand biased 'G'.C hypermutation in human immunoglobulin V(lambda) gene segments suggests that both DNA strands are targets for deamination by activation-induced cytidine deaminase. Mol Immunol. 2004;40:1273-8 pubmed..We suggest that both DNA strands are deaminated and that the transcribed strand is preferentially deaminated in human IgV(lambda) resulting in bias towards mutations from G. ..
- Chaudhuri J, Alt F. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat Rev Immunol. 2004;4:541-52 pubmed
- Wang C, Yang D, Wabl M. Directed molecular evolution by somatic hypermutation. Protein Eng Des Sel. 2004;17:659-64 pubmed..Our results demonstrate in principle that immunoglobulin somatic hypermutation can be a potent means of mutagenesis...
- Masuda K, Ouchida R, Hikida M, Kurosaki T, Yokoi M, Masutani C, et al. DNA polymerases eta and theta function in the same genetic pathway to generate mutations at A/T during somatic hypermutation of Ig genes. J Biol Chem. 2007;282:17387-94 pubmed..These results reveal genetic and biochemical interactions between POLH and POLQ and suggest that POLQ might cooperate with POLH to generate some of the A/T mutations during the somatic hypermutation of Ig genes. ..
- Zan H, Zhang J, Ardeshna S, Xu Z, Park S, Casali P. Lupus-prone MRL/faslpr/lpr mice display increased AID expression and extensive DNA lesions, comprising deletions and insertions, in the immunoglobulin locus: concurrent upregulation of somatic hypermutation and class switch DNA recombination. Autoimmunity. 2009;42:89-103 pubmed publisher
- Martomo S, Saribasak H, Yokoi M, Hanaoka F, Gearhart P. Reevaluation of the role of DNA polymerase theta in somatic hypermutation of immunoglobulin genes. DNA Repair (Amst). 2008;7:1603-8 pubmed publisher..These results indicate that polymerase theta does not play a significant role in the generation of somatic mutation in immunoglobulin genes. ..
- Seki M, Gearhart P, Wood R. DNA polymerases and somatic hypermutation of immunoglobulin genes. EMBO Rep. 2005;6:1143-8 pubmed..The low-fidelity enzyme POLQ has been proposed as another candidate polymerase because it can efficiently bypass abasic sites and recent evidence indicates that it might participate in hypermutation. ..
- Schrader C, Linehan E, Mochegova S, Woodland R, Stavnezer J. Inducible DNA breaks in Ig S regions are dependent on AID and UNG. J Exp Med. 2005;202:561-8 pubmed..Our results indicate that AID attacks cytosines on both DNA strands, and staggered breaks are processed to blunt DSBs at the initiating ss break sites. We propose a model to explain the types of end-processing events observed. ..
- Ross A, Sale J. The catalytic activity of REV1 is employed during immunoglobulin gene diversification in DT40. Mol Immunol. 2006;43:1587-94 pubmed..Thus, the polymerase selection or stabilisation role of REV1 does not appear to play a major role in the bypass of AID-dependent abasic sites. ..
- Zheng N, Wilson K, Jared M, Wilson P. Intricate targeting of immunoglobulin somatic hypermutation maximizes the efficiency of affinity maturation. J Exp Med. 2005;201:1467-78 pubmed..The complexity of these evolved biases in codon use are compounded by the precise concomitant hotspot/coldspot targeting of AID activity and Poleta errors to maximize SHM in the CDRs and minimize mutations in the FWRs. ..
- Shimizu T, Azuma T, Ishiguro M, Kanjo N, Yamada S, Ohmori H. Normal immunoglobulin gene somatic hypermutation in Pol kappa-Pol iota double-deficient mice. Immunol Lett. 2005;98:259-64 pubmed..We found that the double-deficient mice had the normal SHM frequency and profile, rendering them indistinguishable from Polkappa-deficient mice and thus conclude that Poliota and Polkappa are dispensable for SHM in mice. ..
- Chaudhuri J, Basu U, Zarrin A, Yan C, Franco S, Perlot T, et al. Evolution of the immunoglobulin heavy chain class switch recombination mechanism. Adv Immunol. 2007;94:157-214 pubmed
- Schenten D, Kracker S, Esposito G, Franco S, Klein U, Murphy M, et al. Pol zeta ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability. J Exp Med. 2009;206:477-90 pubmed publisher..Based on our results, we suggest a nonredundant role of Pol zeta in DNA DSB repair through nonhomologous end joining. ..
- Martomo S, Yang W, Vaisman A, Maas A, Yokoi M, Hoeijmakers J, et al. Normal hypermutation in antibody genes from congenic mice defective for DNA polymerase iota. DNA Repair (Amst). 2006;5:392-8 pubmed..Thus, polymerase iota did not contribute to the mutational spectra, even in the absence of polymerase eta...
- Pauklin S, Sernández I, Bachmann G, Ramiro A, Petersen Mahrt S. Estrogen directly activates AID transcription and function. J Exp Med. 2009;206:99-111 pubmed publisher..We therefore suggest that estrogen-induced autoimmunity and oncogenesis may be derived through AID-dependent DNA instability. ..
- Jansen J, Langerak P, Tsaalbi Shtylik A, van den Berk P, Jacobs H, de Wind N. Strand-biased defect in C/G transversions in hypermutating immunoglobulin genes in Rev1-deficient mice. J Exp Med. 2006;203:319-23 pubmed..In addition, loss of Rev1 causes compensatory increase in mutagenesis by other translesion synthesis polymerases. ..
- Wright B, Schmidt K, Davis N, Hunt A, Minnick M. II. Correlations between secondary structure stability and mutation frequency during somatic hypermutation. Mol Immunol. 2008;45:3600-8 pubmed publisher..These circumstances simplify the complexities of coordinating mutagenesis by confining this process to each mutable site successively, as they form in response to increasing levels of transcription during affinity maturation. ..
- Saribasak H, Saribasak N, Ipek F, Ellwart J, Arakawa H, Buerstedde J. Uracil DNA glycosylase disruption blocks Ig gene conversion and induces transition mutations. J Immunol. 2006;176:365-71 pubmed..This suggests that hypermutating B cells process activation-induced cytidine deaminase-induced uracils with approximately one-seventh of uracils giving rise to mutations depending on their position. ..
- Honjo T, Nagaoka H, Shinkura R, Muramatsu M. AID to overcome the limitations of genomic information. Nat Immunol. 2005;6:655-61 pubmed..Although a series of experiments has provided support for the 'RNA-editing' hypothesis and requires reevaluation of the 'DNA-deamination' hypothesis, definitive proof is yet to come. ..
- Muto T, Okazaki I, Yamada S, Tanaka Y, Kinoshita K, Muramatsu M, et al. Negative regulation of activation-induced cytidine deaminase in B cells. Proc Natl Acad Sci U S A. 2006;103:2752-7 pubmed
- Xue K, Rada C, Neuberger M. The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2-/- ung-/- mice. J Exp Med. 2006;203:2085-94 pubmed
- Shen H, Tanaka A, Bozek G, Nicolae D, Storb U. Somatic hypermutation and class switch recombination in Msh6(-/-)Ung(-/-) double-knockout mice. J Immunol. 2006;177:5386-92 pubmed
- Teng G, Hakimpour P, Landgraf P, Rice A, Tuschl T, Casellas R, et al. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity. 2008;28:621-9 pubmed publisher..Thus, miR-155, which has recently been shown to play important roles in regulating the germinal-center reaction, does so in part by directly downmodulating AID expression. ..
- Chaudhuri J, Khuong C, Alt F. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature. 2004;430:992-8 pubmed..We propose that B-cell-specific AID-RPA complexes preferentially bind to ssDNA of small transcription bubbles at SHM 'hotspots', leading to AID-mediated deamination and RPA-mediated recruitment of DNA repair proteins. ..
- Rossi D, Berra E, Cerri M, Deambrogi C, Barbieri C, Franceschetti S, et al. Aberrant somatic hypermutation in transformation of follicular lymphoma and chronic lymphocytic leukemia to diffuse large B-cell lymphoma. Haematologica. 2006;91:1405-9 pubmed..Our findings demonstrate that acquisition of novel mutations due to aberrant somatic hypermutation was associated with DLBCL transformation in 5/9 (55.5%) cases of FL and 2/9 (22.2%) cases of B-CLL. ..
- Kotani A, Okazaki I, Muramatsu M, Kinoshita K, Begum N, Nakajima T, et al. A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression. Proc Natl Acad Sci U S A. 2005;102:4506-11 pubmed..SHM base specificities in the CD4 and CD5 genes were biased to AT, indicating that the preference of target bases of the mutations generated by overexpression of AID is not always GC bases but variable between target genes. ..