Activation-Induced Cytidine Deaminase Targets DNA at Sites of RNA Polymerase II Stalling by Interaction with Spt5

Activation-induced cytidine deaminase (AID) initiates antibody gene diversification by creating U:G mismatches. However, AID is not specific for antibody genes; Off-target lesions can activate oncogenes or cause chromosome translocations. Despite its importance in these transactions little is known...

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Bibliographic Details
Published in:Cell 2010-10, Vol.143 (1), p.122-133
Main Authors: Pavri, Rushad, Gazumyan, Anna, Jankovic, Mila, Di Virgilio, Michela, Klein, Isaac, Ansarah-Sobrinho, Camilo, Resch, Wolfgang, Yamane, Arito, San-Martin, Bernardo Reina, Barreto, Vasco, Nieland, Thomas J., Root, David E., Casellas, Rafael, Nussenzweig, Michel C.
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - metabolism
Biochemistry, Molecular Biology
Cell Line
Cell Line, Tumor
Chromosomal Proteins, Non-Histone - metabolism
Cytidine Deaminase - metabolism
DNA
Fibroblasts - metabolism
Humans
Immunoglobulin Class Switching
Immunoglobulins - genetics
Life Sciences
Mice
MOLIMMUNO
RNA Polymerase II - metabolism
Transcriptional Elongation Factors - metabolism
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Summary:Activation-induced cytidine deaminase (AID) initiates antibody gene diversification by creating U:G mismatches. However, AID is not specific for antibody genes; Off-target lesions can activate oncogenes or cause chromosome translocations. Despite its importance in these transactions little is known about how AID finds its targets. We performed an shRNA screen to identify factors required for class switch recombination (CSR) of antibody loci. We found that Spt5, a factor associated with stalled RNA polymerase II (Pol II) and single stranded DNA (ssDNA), is required for CSR. Spt5 interacts with AID, it facilitates association between AID and Pol II, and AID recruitment to its Ig and non-Ig targets. ChIP-seq experiments reveal that Spt5 colocalizes with AID and stalled Pol II. Further, Spt5 accumulation at sites of Pol II stalling is predictive of AID-induced mutation. We propose that AID is targeted to sites of Pol II stalling in part via its association with Spt5. [Display omitted] ► The Pol II stalling factor, Spt5, is required for CSR ► Spt5 interaction with AID is important for AID-Pol II association ► Spt5 colocalizes with AID at sites of Pol II stalling genome-wide in B cells ► Sites of high-density Spt5 and Pol II stalling are predictive of AID-mediated mutation
ISSN:0092-8674
1097-4172
1097-4172
DOI:10.1016/j.cell.2010.09.017