The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates.
Activation-induced cytidine deaminase (AID) initiates immunoglobulin (Ig) heavy-chain (IgH) class switch recombination (CSR) and Ig variable region somatic hypermutation (SHM) in B lymphocytes by deaminating cytidines on template and nontemplate strands of transcribed DNA substrates. However, the mechanism of AID access to the template DNA strand, particularly when hybridized to a nascent RNA transcript, has been an enigma. We now implicate the RNA exosome, a cellular RNA-processing/degradation complex, in targeting AID to both DNA strands. In B lineage cells activated for CSR, the RNA exosome associates with AID, accumulates on IgH switch regions in an AID-dependent fashion, and is required for optimal CSR. Moreover, both the cellular RNA exosome complex and a recombinant RNA exosome core complex impart robust AID- and transcription-dependent DNA deamination of both strands of transcribed SHM substrates in vitro. Our findings reveal a role for noncoding RNA surveillance machinery in generating antibody diversity.
Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Immune Disease Institute, Children's Hospital Boston, Department of Genetics, Harvard Medical School, MA 02115, USA. ub2121@columbia.edu
Uttiya
U
Basu
Fei-Long
FL
Meng
Celia
C
Keim
Veronika
V
Grinstein
Evangelos
E
Pefanis
Jennifer
J
Eccleston
Tingting
T
Zhang
Darienne
D
Myers
Caitlyn R
CR
Wasserman
Duane R
DR
Wesemann
Kurt
K
Januszyk
Richard I
RI
Gregory
Haiteng
H
Deng
Christopher D
CD
Lima
Frederick W
FW
Alt
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000378:metabolism*; D005095:Exoribonucleases / Q000378:metabolism*; D006801:Humans; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D014158:Transcription, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D007143:Immunoglobulin Heavy Chains; D009097:Multienzyme Complexes; D012313:RNA; D005095:Exoribonucleases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
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