Role of genomic instability and p53 in AID-induced c-myc-Igh translocations.
Chromosomal translocations involving the immunoglobulin switch region are a hallmark feature of B-cell malignancies. However, little is known about the molecular mechanism by which primary B cells acquire or guard against these lesions. Here we find that translocations between c-myc and the IgH locus (Igh) are induced in primary B cells within hours of expression of the catalytically active form of activation-induced cytidine deaminase (AID), an enzyme that deaminates cytosine to produce uracil in DNA. Translocation also requires uracil DNA glycosylase (UNG), which removes uracil from DNA to create abasic sites that are then processed to double-strand breaks. The pathway that mediates aberrant joining of c-myc and Igh differs from intrachromosomal repair during immunoglobulin class switch recombination in that it does not require histone H2AX, p53 binding protein 1 (53BP1) or the non-homologous end-joining protein Ku80. In addition, translocations are inhibited by the tumour suppressors ATM, Nbs1, p19 (Arf) and p53, which is consistent with activation of DNA damage- and oncogenic stress-induced checkpoints during physiological class switching. Finally, we demonstrate that accumulation of AID-dependent, IgH-associated chromosomal lesions is not sufficient to enhance c-myc-Igh translocations. Our findings reveal a pathway for surveillance and protection against AID-dependent DNA damage, leading to chromosomal translocations.
Ramiro
Almudena R
AR
Laboratory of Molecular Immunology, The Rockefeller University, Universidad Autonoma de Madrid, Madrid 28049, Spain.
Jankovic
Mila
M
Callen
Elsa
E
Difilippantonio
Simone
S
Chen
Hua-Tang
HT
McBride
Kevin M
KM
Eisenreich
Thomas R
TR
Chen
Junjie
J
Dickins
Ross A
RA
Lowe
Scott W
SW
Nussenzweig
Andre
A
Nussenzweig
Michel C
MC
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D015870:Gene Expression; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics*; D017578:Immunoglobulin Class Switching / Q000235:genetics; D051379:Mice; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D016159:Tumor Suppressor Protein p53; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase