Mechanisms promoting translocations in editing and switching peripheral B cells.
Variable, diversity and joining gene segment (V(D)J) recombination assembles immunoglobulin heavy or light chain (IgH or IgL) variable region exons in developing bone marrow B cells, whereas class switch recombination (CSR) exchanges IgH constant region exons in peripheral B cells. Both processes use directed DNA double-strand breaks (DSBs) repaired by non-homologous end-joining (NHEJ). Errors in either V(D)J recombination or CSR can initiate chromosomal translocations, including oncogenic IgH locus (Igh) to c-myc (also known as Myc) translocations of peripheral B cell lymphomas. Collaboration between these processes has also been proposed to initiate translocations. However, the occurrence of V(D)J recombination in peripheral B cells is controversial. Here we show that activated NHEJ-deficient splenic B cells accumulate V(D)J-recombination-associated breaks at the lambda IgL locus (Igl), as well as CSR-associated Igh breaks, often in the same cell. Moreover, Igl and Igh breaks are frequently joined to form translocations, a phenomenon associated with specific Igh-Igl co-localization. Igh and c-myc also co-localize in these cells; correspondingly, the introduction of frequent c-myc DSBs robustly promotes Igh-c-myc translocations. Our studies show peripheral B cells that attempt secondary V(D)J recombination, and determine a role for mechanistic factors in promoting recurrent translocations in tumours.
Wang
Jing H
JH
Howard Hughes Medical Institute, USA.
Gostissa
Monica
M
Yan
Catherine T
CT
Goff
Peter
P
Hickernell
Thomas
T
Hansen
Erica
E
Difilippantonio
Simone
S
Wesemann
Duane R
DR
Zarrin
Ali A
AA
Rajewsky
Klaus
K
Nussenzweig
Andre
A
Alt
Frederick W
FW
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics*; D005803:Genes, Immunoglobulin / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007399:Interphase; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D017464:Receptors, Complement 3d / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014178:Translocation, Genetic / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007143:Immunoglobulin Heavy Chains; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; C499308:Rag2 protein, mouse; D017464:Receptors, Complement 3d; C511788:XRCC4 protein, mouse; C064658:RAG-1 protein; C045073:Cre recombinase; D019426:Integrases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase