title: The RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage.
abstract: Tight control of antigen-receptor gene rearrangement is required to preserve genome integrity and prevent the occurrence of leukaemia and lymphoma. Nonetheless, mistakes can happen, leading to the generation of aberrant rearrangements, such as Tcra/d-Igh inter-locus translocations that are a hallmark of ataxia telangiectasia-mutated (ATM) deficiency. Current evidence indicates that these translocations arise from the persistence of unrepaired breaks converging at different stages of thymocyte differentiation. Here we show that a defect in feedback control of RAG2 activity gives rise to bi-locus breaks and damage on Tcra/d and Igh in the same T cell at the same developmental stage, which provides a direct mechanism for generating these inter-locus rearrangements. Both the RAG2 C-terminus and ATM prevent bi-locus RAG-mediated cleavage through modulation of three-dimensional conformation (higher-order loops) and nuclear organization of the two loci. This limits the number of potential substrates for translocation and provides an important mechanism for protecting genome stability.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Chaumeil
authors.forename: Mariann
authors.initials: M
authors.lastname: Micsinai
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Ntziachristos
authors.forename: David B
authors.initials: DB
authors.lastname: Roth
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.forename: Yuval
authors.initials: Y
authors.lastname: Kluger
authors.forename: Ludovic
authors.initials: L
authors.lastname: Deriano
authors.forename: Jane A
authors.initials: JA
authors.lastname: Skok
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D016694:Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; D056426:Genetic Loci; D042822:Genomic Instability; D051379:Mice; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D064007:Ataxia Telangiectasia Mutated Proteins
references.citation: Immunity. 2007 Oct;27(4):561-71
references.pmid: 17936034
references.citation: Blood. 2000 Sep 1;96(5):1940-6
references.pmid: 10961898
references.citation: Oncogene. 2007 Dec 10;26(56):7759-64
references.pmid: 18066088
references.citation: Cell Cycle. 2009 Aug;8(15):2408-12
references.pmid: 19556863
references.citation: J Vis Exp. 2013 Feb 03;(72):e50087
references.pmid: 23407477
references.citation: Genes Dev. 1999 Dec 1;13(23):3070-80
references.pmid: 10601033
references.citation: Semin Cancer Biol. 2007 Feb;17(1):80-90
references.pmid: 17137790
references.citation: Nature. 2007 Sep 27;449(7161):483-6
references.pmid: 17898768
references.citation: Nat Genet. 2010 Jan;42(1):53-61
references.pmid: 20010836
references.citation: Science. 2000 Dec 8;290(5498):1962-5
references.pmid: 11110662
references.citation: Nat Genet. 2006 Nov;38(11):1348-54
references.pmid: 17033623
references.citation: Nature. 2011 Mar 3;471(7336):119-23
references.pmid: 21368836
references.citation: Curr Opin Immunol. 2009 Apr;21(2):133-9
references.pmid: 19362456
references.citation: Mol Cell. 2001 Jan;7(1):65-75
references.pmid: 11172712
references.citation: Cell. 2010 Apr 30;141(3):419-31
references.pmid: 20398922
references.citation: Mol Cell Biol. 2003 Apr;23(7):2556-63
references.pmid: 12640136
references.citation: PLoS Biol. 2007 Aug;5(8):e192
references.pmid: 17622196
references.citation: Cell. 2007 Jul 13;130(1):63-75
references.pmid: 17599403
references.citation: Nat Immunol. 2009 Jun;10(6):655-64
references.pmid: 19448632
references.citation: J Immunol. 2012 Jun 15;188(12):6084-92
references.pmid: 22581861
references.citation: Nat Rev Mol Cell Biol. 2009 Apr;10(4):243-54
references.pmid: 19277046
references.citation: Cell. 2012 Mar 2;148(5):908-21
references.pmid: 22341456
references.citation: PLoS Genet. 2012 Jan;8(1):e1002465
references.pmid: 22275876
references.citation: Nature. 2007 Dec 13;450(7172):1106-10
references.pmid: 18033247
references.citation: Nat Rev Immunol. 2010 Sep;10(9):657-63
references.pmid: 20725107
references.citation: Cell. 2004 Apr 16;117(2):171-84
references.pmid: 15084256
references.citation: Cell. 2011 Jan 21;144(2):214-26
references.pmid: 21241892
references.citation: Nucleic Acids Res. 2008 Oct;36(18):5750-62
references.pmid: 18776220
references.citation: Cell Rep. 2013 Feb 21;3(2):359-70
references.pmid: 23416051
references.citation: Nature. 2012 Feb 07;484(7392):69-74
references.pmid: 22314321
references.citation: Nucleic Acids Res. 2004 Aug 24;32(15):4539-49
references.pmid: 15328366
references.citation: J Immunol. 1999 Mar 1;162(5):2575-80
references.pmid: 10072498
references.citation: Curr Opin Cell Biol. 2007 Jun;19(3):311-6
references.pmid: 17467967
references.citation: Nat Rev Immunol. 2011 Apr;11(4):251-63
references.pmid: 21394103
references.citation: Nature. 2006 Jul 27;442(7101):466-70
references.pmid: 16799570
references.citation: Immunity. 2002 Nov;17(5):639-51
references.pmid: 12433370
references.citation: Mol Cell Biol. 1999 Apr;19(4):3010-7
references.pmid: 10082568
references.citation: Nat Biotechnol. 2011 Dec 25;30(1):90-8
references.pmid: 22198700
references.citation: Cell. 1992 Mar 6;68(5):855-67
references.pmid: 1547487
references.citation: Mol Cell. 2001 Jan;7(1):77-87
references.pmid: 11172713
references.citation: Genes Dev. 1999 Dec 1;13(23):3059-69
references.pmid: 10601032
references.citation: Immunol Res. 2008;41(2):103-22
references.pmid: 18214391
references.citation: Nat Med. 2012 Feb 06;18(2):298-301
references.pmid: 22237151
references.citation: Nature. 2007 May 24;447(7143):413-7
references.pmid: 17522674
references.citation: Proc Natl Acad Sci U S A. 2011 May 31;108(22):E149-58
references.pmid: 21551099
references.citation: Science. 1990 Jun 22;248(4962):1517-23
references.pmid: 2360047
references.citation: Nature. 2008 Nov 27;456(7221):529-33
references.pmid: 18931658
references.citation: Annu Rev Immunol. 2012;30:175-202
references.pmid: 22224778
references.citation: Genes Dev. 2011 Jul 1;25(13):1371-83
references.pmid: 21690198
references.citation: J Exp Med. 2010 Jul 5;207(7):1369-80
references.pmid: 20566716
references.citation: Cell. 1996 Oct 18;87(2):253-62
references.pmid: 8861909
references.citation: J Biol Chem. 1998 Mar 6;273(10):5858-68
references.pmid: 9488723
references.citation: Arch Immunol Ther Exp (Warsz). 2009 Mar-Apr;57(2):105-16
references.pmid: 19333736
references.citation: Nature. 1981 Apr 16;290(5807):565-70
references.pmid: 6783962
references.citation: Mol Cell. 2012 Sep 28;47(6):873-85
references.pmid: 22864115
references.citation: Nat Immunol. 2012 Dec;13(12):1196-204
references.pmid: 23064439