Interplay between Target Sequences and Repair Pathways Determines Distinct Outcomes of AID-Initiated Lesions

The Journal of Immunology : Official Journal of the American Association of Immunologists
Zhangguo ChenJing H Wang

Abstract

Activation-induced deaminase (AID) functions by deaminating cytosines and causing U:G mismatches, a rate-limiting step of Ab gene diversification. However, precise mechanisms regulating AID deamination frequency remain incompletely understood. Moreover, it is not known whether different sequence contexts influence the preferential access of mismatch repair or uracil glycosylase (UNG) to AID-initiated U:G mismatches. In this study, we employed two knock-in models to directly compare the mutability of core Sμ and VDJ exon sequences and their ability to regulate AID deamination and subsequent repair process. We find that the switch (S) region is a much more efficient AID deamination target than the V region. Igh locus AID-initiated lesions are processed by error-free and error-prone repair. S region U:G mismatches are preferentially accessed by UNG, leading to more UNG-dependent deletions, enhanced by mismatch repair deficiency. V region mutation hotspots are largely determined by AID deamination. Recurrent and conserved S region motifs potentially function as spacers between AID deamination hotspots. We conclude that the pattern of mutation hotspots and DNA break generation is influenced by sequence-intrinsic properties, which re...Continue Reading

References

Nov 1, 1992·The Biochemical Journal·A VerriF Focher
Aug 31, 1995·Nature·S D WagnerM S Neuberger
Mar 1, 1997·Immunity·E SonodaK Rajewsky
Jan 31, 1998·The Journal of Experimental Medicine·P C WilsonV Pascual
Jul 22, 1998·Proceedings of the National Academy of Sciences of the United States of America·C MilsteinR Staden
Aug 18, 2000·Mutation Research·S S ParikhJ A Tainer
Mar 3, 2001·Current Opinion in Immunology·H Jacobs, L Bross
May 29, 2001·Nature Immunology·I B RogozinT A Kunkel
Jul 13, 2002·Proceedings of the National Academy of Sciences of the United States of America·Darryll D DudleyFrederick W Alt
Jun 18, 2003·The Journal of Experimental Medicine·Bernardo Reina-San-MartinMichel C Nussenzweig
Jul 2, 2004·Nature Reviews. Immunology·Jayanta Chaudhuri, Frederick W Alt
Feb 16, 2006·The Journal of Experimental Medicine·Jacob G JansenNiels de Wind
Dec 22, 2006·European Journal of Immunology·Bernardo Reina-San-MartinMichel C Nussenzweig
Dec 28, 2006·The Journal of Experimental Medicine·Michael S Neuberger, Cristina Rada
Mar 3, 2007·Annual Review of Biochemistry·Javier M Di Noia, Michael S Neuberger
Jun 15, 2007·Advances in Immunology·Jayanta ChaudhuriFrederick W Alt
Nov 21, 2007·The Journal of Experimental Medicine·Jeroen E J GuikemaCarol E Schrader
Nov 18, 2008·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Carol E SchraderJanet Stavnezer
Mar 24, 2009·Trends in Immunology·Man Liu, David G Schatz
May 13, 2009·The Journal of Experimental Medicine·Deepa RajagopalPatricia J Gearhart
Jun 26, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jennifer EcclestonErik Selsing
Aug 24, 2010·Nature Structural & Molecular Biology·Zhenming XuPaolo Casali
Apr 16, 2011·Trends in Immunology·Janet Stavnezer
Apr 12, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lucia KatoTasuku Honjo
Jun 6, 2012·The Journal of Experimental Medicine·Pablo Pérez-DuránAlmudena R Ramiro
Jun 19, 2012·Seminars in Immunology·Richard ChahwanSergio Roa
Sep 11, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Zhangguo ChenJing H Wang
Apr 22, 2014·Frontiers of Medicine·Zhangguo Chen, Jing H Wang
Oct 24, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Zhangguo ChenJing H Wang

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Citations

Jan 1, 2017·Nucleic Acids Research·Eddy Sanchai ThientosapolChristopher J Jolly
Apr 20, 2018·Proceedings of the National Academy of Sciences of the United States of America·Eddy Sanchai ThientosapolChristopher J Jolly

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