Constitutive expression of AID leads to tumorigenesis.
Genome stability is regulated by the balance between efficiencies of the repair machinery and genetic alterations such as mutations and chromosomal rearrangements. It has been postulated that deregulation of class switch recombination (CSR) and somatic hypermutation (SHM), which modify the immunoglobulin (Ig) genes in activated B cells, may be responsible for aberrant chromosomal translocations and mutations of non-Ig genes that lead to lymphocyte malignancy. However, the molecular basis for these genetic instabilities is not clearly understood. Activation-induced cytidine deaminase (AID) is shown to be essential and sufficient to induce both CSR and SHM in artificial substrates in fibroblasts as well as B cells. Here we show that constitutive and ubiquitous expression of AID in transgenic mice caused both T cell lymphomas and dysgenetic lesions of epithelium of respiratory bronchioles (micro-adenomas) in all individual mice. Point mutations, but not translocations, were massively introduced in expressed T cell receptor (TCR) and c-myc genes in T lymphoma cells. The results indicate that AID can mutate non-Ig genes including oncogenes, implying that aberrant AID expression could be a cause of human malignancy.
Department of Medical Chemistry and Molecular Biology, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Il-mi
IM
Okazaki
Hiroshi
H
Hiai
Naoki
N
Kakazu
Shuichi
S
Yamada
Masamichi
M
Muramatsu
Kazuo
K
Kinoshita
Tasuku
T
Honjo
D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D002471:Cell Transformation, Neoplastic; D003564:Cytidine Deaminase / Q000378:metabolism*; D017931:DNA Primers; D005434:Flow Cytometry; D008221:Lymphoid Tissue / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D017354:Point Mutation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D017931:DNA Primers; D011948:Receptors, Antigen, T-Cell; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase