IgH class switching and translocations use a robust non-classical end-joining pathway

被引:455
作者
Yan, Catherine T.
Boboila, Cristian
Souza, Ellen Kris
Franco, Sonia
Hickernell, Thomas R.
Murphy, Michael
Gumaste, Sunil
Geyer, Mark
Zarrin, Ali A.
Manis, John P.
Rajewsky, Klaus
Alt, Frederick W. [1 ]
机构
[1] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA
[5] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
关键词
D O I
10.1038/nature06020
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Immunoglobulin variable region exons are assembled in developing B cells by V(D)J recombination. Once mature, these cells undergo class-switch recombination (CSR) when activated by antigen. CSR changes the heavy chain constant region exons (CH) expressed with a given variable region exon from Cm to a downstream CH (for example, C gamma, C epsilon or C alpha), thereby switching expression from IgM to IgG, IgE or IgA. Both V(D)J recombination and CSR involve the introduction of DNA double-strand breaks and their repair by means of end joining(1,2). For CSR, double-strand breaks are introduced into switch regions that flank Cm and a downstream CH, followed by fusion of the broken switch regions(1). In mammalian cells, the 'classical' non-homologous end joining (C-NHEJ) pathway repairs both general DNA double-strand breaks and programmed double-strand breaks generated by V(D)J recombination(2,3). C-NHEJ, as observed during V(D)J recombination, joins ends that lack homology to form 'direct' joins, and also joins ends with several base-pair homologies to form microhomology joins(3,4). CSR joins also display direct and microhomology joins, and CSR has been suggested to use C-NHEJ(5-8). Xrcc4 and DNA ligase IV (Lig4), which cooperatively catalyse the ligation step of C-NHEJ, are the most specific C-NHEJ factors; they are absolutely required for V(D)J recombination and have no known functions other than C-NHEJ(2). Here we assess whether C-NHEJ is also critical for CSR by assaying CSR in Xrcc4- or Lig4-deficient mouse B cells. C-NHEJ indeed catalyses CSR joins, because C-NHEJ-deficient B cells had decreased CSR and substantial levels of IgH locus (immunoglobulin heavy chain, encoded by Igh) chromosomal breaks. However, an alternative end-joining pathway, which is markedly biased towards microhomology joins, supports CSR at unexpectedly robust levels in C-NHEJ-deficient B cells. In the absence of C-NHEJ, this alternative end-joining pathway also frequently joins Igh locus breaks to other chromosomes to generate translocations.
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页码:478 / U9
页数:6
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