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PMID: 21255825 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates.

Cell ·Vol. 144 ·No. 3 ·2011-02-04 ·Pages 353-63

Basu U, Meng FL, Keim C, Grinstein V, Pefanis E, Eccleston J, Zhang T, Myers D, Wasserman CR, Wesemann DR, Januszyk K, Gregory RI, Deng H, Lima CD, Alt FW

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.

MeSH Terms
Animals B-Lymphocytes/cytology,enzymology,metabolism Cell Line Cells, Cultured Cytidine Deaminase/metabolism Exoribonucleases/metabolism Humans Immunoglobulin Class Switching Immunoglobulin Heavy Chains/genetics Mice Multienzyme Complexes/metabolism RNA/metabolism Transcription, Genetic
Chemicals
Immunoglobulin Heavy Chains Multienzyme Complexes RNA Exoribonucleases AICDA (activation-induced cytidine deaminase) Cytidine Deaminase
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Basu Uttiya
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
Meng Fei-Long
Keim Celia
Grinstein Veronika
Pefanis Evangelos
Eccleston Jennifer
Zhang Tingting
Myers Darienne
Wasserman Caitlyn R
Wesemann Duane R
Januszyk Kurt
Gregory Richard I
Deng Haiteng
Lima Christopher D
Alt Frederick W
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2011.01.001
Email
ub2121@columbia.edu
Published
2011-02-04
Epub
2011-00-20
Pages
353-63
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3065114
Subset
IM
Grants
NIGMS NIH HHS · R01 GM079196-04 · United States
NIGMS NIH HHS · R01 GM079196-03 · United States
NIGMS NIH HHS · R01 GM079196 · United States
NCI NIH HHS · T32 CA009503 · United States
NIAID NIH HHS · P01 AI031541 · United States
NIAID NIH HHS · R01 AI077595 · United States
NIAID NIH HHS · R37 AI077595 · United States
NIGMS NIH HHS · R01 GM079196-01A1 · United States
NIGMS NIH HHS · R01 GM079196-02 · United States
NCI NIH HHS · CA09503-23 · United States
NIGMS NIH HHS · GM079196 · United States
NIAID NIH HHS · U19 AI031541 · United States
NIAID NIH HHS · R01 AI077595-04 · United States
NIAID NIH HHS · AI31541 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2011.01.001 PMC Full Text View journal details
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