title: AIDing Chromatin and Transcription-Coupled Orchestration of Immunoglobulin Class-Switch Recombination.
abstract: Secondary diversification of the antibody repertoire upon antigenic challenge, in the form of immunoglobulin heavy chain (IgH) class-switch recombination (CSR) endows mature, naïve B cells in peripheral lymphoid organs with a limitless ability to mount an optimal humoral immune response, thus expediting pathogen elimination. CSR replaces the default constant (CH) region exons (Cμ) of IgH with any of the downstream CH exons (Cγ, Cε, or Cα), thereby altering effector functions of the antibody molecule. This process depends on, and is orchestrated by, activation-induced deaminase (AID), a DNA cytidine deaminase that acts on single-stranded DNA exposed during transcription of switch (S) region sequences at the IgH locus. DNA lesions thus generated are processed by components of several general DNA repair pathways to drive CSR. Given that AID can instigate DNA lesions and genomic instability, stringent checks are imposed that constrain and restrict its mutagenic potential. In this review, we will discuss how AID expression and substrate specificity and activity is rigorously enforced at the transcriptional, post-transcriptional, post-translational, and epigenetic levels, and how the DNA-damage response is choreographed with precision to permit targeted activity while limiting bystander catastrophe.
authors.affiliation: Weill Cornell Graduate School of Medical Sciences , New York, NY , USA ; Immunology Program, Memorial Sloan Kettering Cancer Center, Gerstner Sloan Kettering Graduate School , New York, NY , USA.
authors.forename: Bharat
authors.initials: B
authors.lastname: Vaidyanathan
authors.affiliation: Weill Cornell Graduate School of Medical Sciences , New York, NY , USA ; Immunology Program, Memorial Sloan Kettering Cancer Center, Gerstner Sloan Kettering Graduate School , New York, NY , USA.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Yen
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, Gerstner Sloan Kettering Graduate School , New York, NY , USA.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Pucella
authors.affiliation: Weill Cornell Graduate School of Medical Sciences , New York, NY , USA ; Immunology Program, Memorial Sloan Kettering Cancer Center, Gerstner Sloan Kettering Graduate School , New York, NY , USA.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Chaudhuri
keywords: DNA recombination; DNA repair; R-loops; class-switching; cytidine deamination
references.citation: J Exp Med. 2003 Jun 16;197(12):1767-78
references.pmid: 12810694
references.citation: Nature. 2003 Apr 17;422(6933):726-30
references.pmid: 12692563
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22375-80
references.pmid: 20018730
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8798-803
references.pmid: 16723391
references.citation: Immunity. 2007 Dec;27(6):847-59
references.pmid: 18055230
references.citation: Genes Dev. 2013 Aug 15;27(16):1821-33
references.pmid: 23964096
references.citation: J Exp Med. 2010 May 10;207(5):983-97
references.pmid: 20385750
references.citation: J Exp Med. 2001 Jan 15;193(2):159-68
references.pmid: 11148220
references.citation: Nature. 2001 Dec 6;414(6864):660-665
references.pmid: 11740565
references.citation: Philos Trans R Soc Lond B Biol Sci. 2009 Mar 12;364(1517):645-52
references.pmid: 19010771
references.citation: Nat Immunol. 2010 Feb;11(2):107-9
references.pmid: 20084065
references.citation: PLoS One. 2013 Nov 25;8(11):e80414
references.pmid: 24282540
references.citation: J Exp Med. 2008 Sep 29;205(10):2199-206
references.pmid: 18762567
references.citation: Nature. 2011 Mar 3;471(7336):119-23
references.pmid: 21368836
references.citation: J Exp Med. 2003 May 19;197(10):1291-6
references.pmid: 12756266
references.citation: Nat Immunol. 2010 Sep;11(9):820-6
references.pmid: 20657597
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3843-8
references.pmid: 18292225
references.citation: J Exp Med. 2013 May 6;210(5):1021-33
references.pmid: 23589568
references.citation: Mol Cell. 2004 Oct 22;16(2):163-71
references.pmid: 15494304
references.citation: Nat Immunol. 2011 Jan;12(1):70-6
references.pmid: 21151102
references.citation: Nature. 2010 Feb 25;463(7284):1101-5
references.pmid: 20098412
references.citation: Mol Cell. 2012 Dec 14;48(5):760-70
references.pmid: 23142080
references.citation: Science. 2002 Jun 14;296(5575):2033-6
references.pmid: 12065838
references.citation: PLoS One. 2013 Jul 08;8(7):e69208
references.pmid: 23861962
references.citation: J Biol Chem. 2000 Aug 4;275(31):24163-72
references.pmid: 10811812
references.citation: Mol Cell. 2013 Nov 21;52(4):583-90
references.pmid: 24211264
references.citation: J Exp Med. 2009 Jan 16;206(1):99-111
references.pmid: 19139166
references.citation: Mol Cell. 2013 Mar 7;49(5):872-83
references.pmid: 23333306
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3040-5
references.pmid: 20133637
references.citation: Nature. 2002 Jul 4;418(6893):99-103
references.pmid: 12097915
references.citation: Nat Immunol. 2012 Sep;13(9):797-8; author reply 798-800
references.pmid: 22910380
references.citation: J Immunol. 1992 Aug 1;149(3):1075-85
references.pmid: 1321850
references.citation: J Immunol. 2013 Dec 1;191(11):5751-63
references.pmid: 24146042
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6736-41
references.pmid: 19351893
references.citation: Nature. 2010 Feb 25;463(7284):1042-7
references.pmid: 20027182
references.citation: Nat Med. 2007 Apr;13(4):470-6
references.pmid: 17401375
references.citation: Nat Immunol. 2011 Feb;12(2):160-6
references.pmid: 21186367
references.citation: J Biol Chem. 2009 Aug 21;284(34):22898-904
references.pmid: 19561087
references.citation: Cell Rep. 2013 Jan 31;3(1):138-47
references.pmid: 23291097
references.citation: J Exp Med. 2011 Aug 1;208(8):1649-60
references.pmid: 21746811
references.citation: Nat Struct Mol Biol. 2011 Jan;18(1):75-9
references.pmid: 21131982
references.citation: Nat Immunol. 2011 Jun;12(6):536-43
references.pmid: 21572431
references.citation: J Exp Med. 2008 Oct 27;205(11):2585-94
references.pmid: 18838546
references.citation: Cell. 2011 Sep 30;147(1):107-19
references.pmid: 21962511
references.citation: Adv Immunol. 2007;94:157-214
references.pmid: 17560275
references.citation: Nature. 2011 Feb 3;470(7332):124-8
references.pmid: 21293379
references.citation: J Exp Med. 2010 May 10;207(5):973-81
references.pmid: 20385748
references.citation: Nature. 2005 Nov 24;438(7067):508-11
references.pmid: 16251902
references.citation: Mol Cell. 2003 Aug;12(2):501-8
references.pmid: 14536088
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2717-22
references.pmid: 19196992
references.citation: Oncogene. 2007 Aug 16;26(38):5587-95
references.pmid: 17404578
references.citation: Nat Immunol. 2013 Nov;14(11):1183-1189
references.pmid: 24097111
references.citation: Nat Immunol. 2003 May;4(5):452-6
references.pmid: 12692548
references.citation: Cell. 2011 Sep 30;147(1):95-106
references.pmid: 21962510
references.citation: Cell. 2004 Apr 16;117(2):171-84
references.pmid: 15084256
references.citation: Cell. 2000 Sep 1;102(5):553-63
references.pmid: 11007474
references.citation: Cell Rep. 2013 Nov 14;5(3):702-714
references.pmid: 24209747
references.citation: Nature. 2010 Apr 15;464(7291):1071-6
references.pmid: 20393566
references.citation: Nature. 2004 Aug 26;430(7003):992-8
references.pmid: 15273694
references.citation: Nat Immunol. 2003 May;4(5):435-41
references.pmid: 12679811
references.citation: Nat Rev Immunol. 2004 Jul;4(7):541-52
references.pmid: 15229473
references.citation: DNA Repair (Amst). 2003 Nov 21;2(11):1163-74
references.pmid: 14599739
references.citation: Nature. 2013 Jun 6;498(7452):70-4
references.pmid: 23708966
references.citation: Nat Immunol. 2011 Jan;12(1):62-9
references.pmid: 21113164
references.citation: J Exp Med. 2010 May 10;207(5):933-42
references.pmid: 20421391
references.citation: Int Immunol. 2004 Apr;16(4):549-57
references.pmid: 15039385
references.citation: PLoS Genet. 2011 Apr;7(4):e1001381
references.pmid: 21552324
references.citation: PLoS One. 2013 Apr 16;8(4):e61433
references.pmid: 23613851
references.citation: Science. 1995 Mar 24;267(5205):1825-8
references.pmid: 7892607
references.citation: J Exp Med. 2002 Feb 4;195(3):367-73
references.pmid: 11828012
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):809-14
references.pmid: 20080757
references.citation: Semin Immunol. 2012 Aug;24(4):246-54
references.pmid: 22687198
references.citation: Annu Rev Biochem. 2007;76:1-22
references.pmid: 17328676
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13130-4
references.pmid: 21788515
references.citation: Mol Cell Biol. 2011 Feb;31(3):442-9
references.pmid: 21135131
references.citation: Cell. 2010 Apr 2;141(1):27-38
references.pmid: 20371343
references.citation: Cell. 2013 Jun 6;153(6):1266-80
references.pmid: 23727112
references.citation: Semin Immunol. 2012 Aug;24(4):281-6
references.pmid: 22784681
references.citation: Cell. 2011 Feb 4;144(3):353-63
references.pmid: 21255825
references.citation: Nat Commun. 2013;4:2231
references.pmid: 23900513
references.citation: J Mol Biol. 2013 Jan 23;425(2):424-43
references.pmid: 23183374
references.citation: Curr Biol. 2002 Oct 15;12(20):1748-55
references.pmid: 12401169
references.citation: Nat Chem Biol. 2012 Sep;8(9):751-8
references.pmid: 22772155
references.citation: Immunity. 2007 Jul;27(1):64-75
references.pmid: 17658280
references.citation: Immunity. 2008 May;28(5):621-9
references.pmid: 18450484
references.citation: J Exp Med. 2013 Jan 14;210(1):115-23
references.pmid: 23254285
references.citation: DNA Repair (Amst). 2007 Feb 4;6(2):235-43
references.pmid: 17161027
references.citation: Cell. 2013 Mar 14;152(6):1344-54
references.pmid: 23498941
references.citation: Nat Struct Mol Biol. 2010 Sep;17(9):1124-35
references.pmid: 20729863
references.citation: Proc Natl Acad Sci U S A. 1990 Oct;87(20):7829-33
references.pmid: 2122447
references.citation: Science. 2003 Dec 19;302(5653):2137-40
references.pmid: 14684824
references.citation: Nat Immunol. 2003 May;4(5):442-51
references.pmid: 12679812
references.citation: Cell. 2013 Jan 31;152(3):417-29
references.pmid: 23374339
references.citation: J Exp Med. 2012 Dec 17;209(13):2455-65
references.pmid: 23166356
references.citation: J Immunol. 2004 Mar 15;172(6):3382-4
references.pmid: 15004135
references.citation: Nature. 2013 Aug 1;500(7460):89-92
references.pmid: 23803762
references.citation: J Immunol. 1993 Nov 1;151(9):4528-33
references.pmid: 8409416
references.citation: Nat Immunol. 2004 Dec;5(12):1275-81
references.pmid: 15531884
references.citation: J Exp Med. 2011 Nov 21;208(12):2385-91
references.pmid: 22042974
references.citation: Nature. 2003 Jul 3;424(6944):103-7
references.pmid: 12819663
references.citation: J Exp Med. 2009 May 11;206(5):1073-87
references.pmid: 19414557
references.citation: Mol Cell Biol. 2013 Apr;33(7):1468-73
references.pmid: 23382073
references.citation: J Biol Chem. 2010 Nov 26;285(48):37797-810
references.pmid: 20855884
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14553-8
references.pmid: 11717399
references.citation: Nat Immunol. 2009 Apr;10(4):420-6
references.pmid: 19234474
references.citation: Science. 2008 Oct 31;322(5902):750-6
references.pmid: 18974356
references.citation: Nat Commun. 2013;4:1830
references.pmid: 23652018
references.citation: Immunity. 2008 May;28(5):630-8
references.pmid: 18455451
references.citation: J Biol Chem. 2004 Dec 10;279(50):52353-60
references.pmid: 15448152
references.citation: J Immunol. 2012 Sep 1;189(5):2374-82
references.pmid: 22826323
references.citation: Mol Cell. 2013 Mar 7;49(5):858-71
references.pmid: 23333305
references.citation: Mol Immunol. 2010 Feb;47(5):961-71
references.pmid: 20036775
references.citation: Cell Cycle. 2009 May 15;8(10):1532-8
references.pmid: 19372751
references.citation: Mol Cell. 2011 Jan 21;41(2):232-42
references.pmid: 21255732
references.citation: J Exp Med. 2009 Aug 3;206(8):1817-30
references.pmid: 19596805
references.citation: J Biol Chem. 2013 Oct 11;288(41):29786-95
references.pmid: 23979486
references.citation: Nature. 2008 Feb 14;451(7180):841-5
references.pmid: 18273020
references.citation: Annu Rev Immunol. 2008;26:261-92
references.pmid: 18370922
references.citation: Blood. 2004 May 15;103(10):3828-36
references.pmid: 14962903
references.citation: Science. 2013 Feb 8;339(6120):700-4
references.pmid: 23306437
references.citation: Cell. 2000 Sep 1;102(5):565-75
references.pmid: 11007475
references.citation: J Immunol. 2009 Jul 15;183(2):1238-44
references.pmid: 19553525
references.citation: Biol Chem. 2013 Nov;394(11):1357-70
references.pmid: 23787464
references.citation: J Exp Med. 1998 Dec 21;188(12):2369-74
references.pmid: 9858523
references.citation: J Immunol. 1993 Feb 15;150(4):1338-47
references.pmid: 8432981
references.citation: J Exp Med. 2012 Oct 22;209(11):2099-111
references.pmid: 23008333
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):395-400
references.pmid: 16387847
references.citation: Adv Immunol. 2012;116:1-49
references.pmid: 23063072
references.citation: Science. 2010 Aug 20;329(5994):917-23
references.pmid: 20671152
references.citation: Cell. 2010 Oct 1;143(1):122-33
references.pmid: 20887897
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12304-8
references.pmid: 12202747
references.citation: Genes Dev. 2013 Nov 15;27(22):2439-44
references.pmid: 24240234
references.citation: Cell. 2009 Dec 11;139(6):1069-83
references.pmid: 19962179
references.citation: Nat Immunol. 2012 Nov;13(11):1083-91
references.pmid: 23001145
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2752-7
references.pmid: 19202054
references.citation: Nat Immunol. 2013 Jul;14(7):749-55
references.pmid: 23708250
references.citation: J Immunol. 2013 Jun 15;190(12):6135-44
references.pmid: 23690468
references.citation: Curr Opin Immunol. 2011 Apr;23(2):184-9
references.pmid: 21295456
references.citation: J Exp Med. 2008 Jun 9;205(6):1357-68
references.pmid: 18474627
references.citation: Immunity. 2007 Nov;27(5):711-22
references.pmid: 17980632