Oncogenic events triggered by AID, the adverse effect of antibody diversification.
The generation of an efficient immune response depends on highly refined mechanisms of antibody diversification. Two of these mechanisms, somatic hypermutation (SHM) and class switch recombination (CSR), are initiated by activation-induced cytidine deaminase (AID) upon antigen stimulation of mature B cells. AID deaminates cytosines on the DNA of Ig genes thereby generating a lesion that can be processed into a mutation (SHM) or a DNA double-strand break followed by a recombination reaction (CSR). A number of mechanisms are probably responsible for regulating AID function, such as transcriptional regulation, subcellular localization, post-transcriptional modifications and target specificity, but the issue remains of how unwanted DNA damage is fully prevented. Most lymphocyte neoplasias are originated from mature B cells and harbour hallmark chromosome translocations of lymphomagenic potential, such as the c-myc/IgH translocations found in Burkitt lymphomas. It has been recently shown that such translocations are initiated by AID and that ataxia-telangiectasia mutated, p53 and ARF provide surveillance mechanisms to prevent these aberrations. In addition, evidence is accumulating that AID expression can be induced in B cells independently of the germinal centre environment, such as in response to some viral infections, and occasionally in non-B cells, at least in certain inflammation-associated neoplasic situations. The most recent findings on AID expression and function and their relevance to the generation of oncogenic lesions will be discussed.
Pérez-Durán
Pablo
P
DNA Hypermutation and Cancer group, Spanish National Research Cancer Center, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
de Yebenes
Virginia G
VG
Ramiro
Almudena R
AR
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin / Q000276:immunology; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D006801:Humans; D017578:Immunoglobulin Class Switching; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology; D011995:Recombination, Genetic; D027041:Somatic Hypermutation, Immunoglobulin; D025521:Tumor Suppressor Proteins / Q000502:physiology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)