Author/Authors :
Uttiya Basu، نويسنده , , Fei-Long Meng، نويسنده , , Celia Keim، نويسنده , , Veronika Grinstein، نويسنده , , Evangelos Pefanis، نويسنده , , Jennifer Eccleston، نويسنده , , Tingting Zhang، نويسنده , , Darienne Myers، نويسنده , , Caitlyn R. Wasserman، نويسنده , , Duane R. Wesemann، نويسنده , , Kurt Januszyk، نويسنده , , Richard I. Gregory، نويسنده , , Haiteng Deng، نويسنده , , Christopher D. Lima، نويسنده , , Frederick W. Alt، نويسنده ,
Abstract :
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.
