A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression.
Activation-induced cytidine deaminase (AID) is essential for somatic hypermutations (SHM) and class switch recombination. Overexpression of AID in non-B cells can induce SHM in artificial constructs inserted in various loci in the genome. AID overexpression was thus proposed to introduce mutations in a wide variety of genes with little specificity. We previously showed that AID transgenic mice developed T cell lymphomas in which the variable region beta genes of the T cell receptor and c-myc were mutated as frequently as SHM in activated B cells. To understand the target specificity of SHM in AID-expressing T lymphomas, we sequenced six oncogenes (c-myc, pim1, p53, atm, tgfbr-2, and k-ras) and two genes (cd4 and cd5) that are actively transcribed in T lymphomas. SHM was found only in c-myc, pim1, cd4, and cd5, which share the E47 binding motif in the enhancer/promoter. The rest that are not mutated in B cells were not mutated in AID-induced T lymphomas either, although they are transcribed in T and B cells. Comparison of several features of SHM, including selection of targets and mutation distribution, suggests that the regulatory mechanism of SHM is similar between T and B cells. SHM base specificities in the CD4 and CD5 genes were biased to AT, indicating that the preference of target bases of the mutations generated by overexpression of AID is not always GC bases but variable between target genes.
Kotani
Ai
A
Department of Medical Chemistry and Molecular Biology, Graduate School of Medicine, Kyoto University, Yoshida Konoe-Cho, Sakyo-Ku, Kyoto 606-8501, Japan.
Okazaki
Il-Mi
IM
Muramatsu
Masamichi
M
Kinoshita
Kazuo
K
Begum
Nasim A
NA
Nakajima
Toshiharu
T
Saito
Hirohisa
H
Honjo
Tasuku
T
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D001482:Base Composition; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000235:genetics*; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D017578:Immunoglobulin Class Switching; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D027041:Somatic Hypermutation, Immunoglobulin; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D004273:DNA, Neoplasm; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase