Mechanism and Regulation of Secondary Immunoglobulin Diversification

Overview

Journal Cell Cycle

Specialty Cell Biology

Date 2023 Nov 1

PMID 37909747

Authors

Amanda Bello

Gianna Hirth

Stefanie Voigt

Sandra Tepper

Berit Jungnickel

Affiliations

Soon will be listed here.

Abstract

Secondary immunoglobulin diversification by somatic hypermutation and class switch recombination in B cells is instrumental for an adequate adaptive humoral immune response. These genetic events may, however, also introduce aberrations into other cellular genes and thereby cause B cell malignancies. While the basic mechanism of somatic hypermutation and class switch recombination is now well understood, their regulation and in particular the mechanism of their specific targeting to immunoglobulin genes is still rather mysterious. In this review, we summarize the current knowledge on the mechanism and regulation of secondary immunoglobulin diversification and discuss known mechanisms of physiological targeting to immunoglobulin genes and mistargeting to other cellular genes. We summarize open questions in the field and provide an outlook on future research.

References

Maeda K, Singh S, Eda K, Kitabatake M, Pham P, Goodman M . GANP-mediated recruitment of activation-induced cytidine deaminase to cell nuclei and to immunoglobulin variable region DNA. J Biol Chem. 2010; 285(31):23945-53. PMC: 2911284. DOI: 10.1074/jbc.M110.131441. View

Yadav A, Olaru A, Saltis M, Setren A, cerny J, Livak F . Identification of a ubiquitously active promoter of the murine activation-induced cytidine deaminase (AICDA) gene. Mol Immunol. 2005; 43(6):529-41. DOI: 10.1016/j.molimm.2005.05.007. View

Rothschild G, Zhang W, Lim J, Giri P, Laffleur B, Chen Y . Noncoding RNA transcription alters chromosomal topology to promote isotype-specific class switch recombination. Sci Immunol. 2020; 5(44). PMC: 7608691. DOI: 10.1126/sciimmunol.aay5864. View

Bello A, Muller A, Hirth G, Giebeler L, Bottcher K, Voigt S . Cell Cycle-Mediated Regulation of Secondary Ig Diversification. J Immunol. 2023; 210(10):1508-1518. DOI: 10.4049/jimmunol.2100880. View

Bottcher K, Braunschmidt K, Hirth G, Scharich K, Klassert T, Stock M . Context-dependent regulation of immunoglobulin mutagenesis by p53. Mol Immunol. 2021; 138:128-136. DOI: 10.1016/j.molimm.2021.08.005. View

Zeng X, Winter D, Kasmer C, Kraemer K, Lehmann A, Gearhart P . DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nat Immunol. 2001; 2(6):537-41. DOI: 10.1038/88740. View

Wang X, Fan M, Kalis S, Wei L, Scharff M . A source of the single-stranded DNA substrate for activation-induced deaminase during somatic hypermutation. Nat Commun. 2014; 5:4137. PMC: 4154566. DOI: 10.1038/ncomms5137. View

Methot S, Litzler L, Subramani P, Eranki A, Fifield H, Patenaude A . A licensing step links AID to transcription elongation for mutagenesis in B cells. Nat Commun. 2018; 9(1):1248. PMC: 5871760. DOI: 10.1038/s41467-018-03387-6. View

Ranjit S, Khair L, Linehan E, Ucher A, Chakrabarti M, Schrader C . AID recruits UNG and Msh2 to Ig switch regions dependent upon the AID C terminus [corrected]. J Immunol. 2011; 187(5):2464-75. PMC: 3159830. DOI: 10.4049/jimmunol.1101406. View

10.

Zheng S, Vuong B, Vaidyanathan B, Lin J, Huang F, Chaudhuri J . Non-coding RNA Generated following Lariat Debranching Mediates Targeting of AID to DNA. Cell. 2015; 161(4):762-73. PMC: 4426339. DOI: 10.1016/j.cell.2015.03.020. View

11.

Park S, Zan H, Pal Z, Zhang J, Al-Qahtani A, Pone E . HoxC4 binds to the promoter of the cytidine deaminase AID gene to induce AID expression, class-switch DNA recombination and somatic hypermutation. Nat Immunol. 2009; 10(5):540-50. PMC: 2753990. DOI: 10.1038/ni.1725. View

12.

Ambrose H, Papadopoulou V, Beswick R, Wagner S . Poly-(ADP-ribose) polymerase-1 (Parp-1) binds in a sequence-specific manner at the Bcl-6 locus and contributes to the regulation of Bcl-6 transcription. Oncogene. 2007; 26(42):6244-52. DOI: 10.1038/sj.onc.1210434. View

13.

Bennett R, Diner E, Sowden M, Lees J, Wedekind J, Smith H . APOBEC-1 and AID are nucleo-cytoplasmic trafficking proteins but APOBEC3G cannot traffic. Biochem Biophys Res Commun. 2006; 350(1):214-9. PMC: 1847397. DOI: 10.1016/j.bbrc.2006.09.032. View

14.

Hasham M, Donghia N, Coffey E, Maynard J, Snow K, Ames J . Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination. Nat Immunol. 2010; 11(9):820-6. PMC: 2930818. DOI: 10.1038/ni.1909. View

15.

Arakawa H, Moldovan G, Saribasak H, Saribasak N, Jentsch S, Buerstedde J . A role for PCNA ubiquitination in immunoglobulin hypermutation. PLoS Biol. 2006; 4(11):e366. PMC: 1618868. DOI: 10.1371/journal.pbio.0040366. View

16.

Ganesh K, Adam S, Taylor B, Simpson P, Rada C, Neuberger M . CTNNBL1 is a novel nuclear localization sequence-binding protein that recognizes RNA-splicing factors CDC5L and Prp31. J Biol Chem. 2011; 286(19):17091-102. PMC: 3089553. DOI: 10.1074/jbc.M110.208769. View

17.

Shlomchik M, Luo W, Weisel F . Linking signaling and selection in the germinal center. Immunol Rev. 2019; 288(1):49-63. PMC: 6422174. DOI: 10.1111/imr.12744. View

18.

Zahn A, Eranki A, Patenaude A, Methot S, Fifield H, Cortizas E . Activation induced deaminase C-terminal domain links DNA breaks to end protection and repair during class switch recombination. Proc Natl Acad Sci U S A. 2014; 111(11):E988-97. PMC: 3964074. DOI: 10.1073/pnas.1320486111. View

19.

Qiao Q, Wang L, Meng F, Hwang J, Alt F, Wu H . AID Recognizes Structured DNA for Class Switch Recombination. Mol Cell. 2017; 67(3):361-373.e4. PMC: 5771415. DOI: 10.1016/j.molcel.2017.06.034. View

20.

Rada C, Ehrenstein M, Neuberger M, Milstein C . Hot spot focusing of somatic hypermutation in MSH2-deficient mice suggests two stages of mutational targeting. Immunity. 1998; 9(1):135-41. DOI: 10.1016/s1074-7613(00)80595-6. View