Meng, Fei-Long, Du, Zhou, Federation, Alexander, Hu, Jiazhi, Wang, Qiao, Kieffer-Kwon, Kyong-Rim, Meyers, Robin M, Amor, Corina, Wasserman, Caitlyn R, Neuberg, Donna, Casellas, Rafael, Nussenzweig, Michel C, Bradner, James E, Liu, X Shirley, Alt, Frederick W (December 2014) Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell, 159 (7). pp. 1538-48. ISSN 1097-4172
Abstract
Activation-induced cytidine deaminase (AID) initiates both somatic hypermutation (SHM) for antibody affinity maturation and DNA breakage for antibody class switch recombination (CSR) via transcription-dependent cytidine deamination of single-stranded DNA targets. Though largely specific for immunoglobulin genes, AID also acts on a limited set of off-targets, generating oncogenic translocations and mutations that contribute to B cell lymphoma. How AID is recruited to off-targets has been a long-standing mystery. Based on deep GRO-seq studies of mouse and human B lineage cells activated for CSR or SHM, we report that most robust AID off-target translocations occur within highly focal regions of target genes in which sense and antisense transcription converge. Moreover, we found that such AID-targeting "convergent" transcription arises from antisense transcription that emanates from super-enhancers within sense transcribed gene bodies. Our findings provide an explanation for AID off-targeting to a small subset of mostly lineage-specific genes in activated B cells.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer > cancer types > B cell lymphoma organs, tissues, organelles, cell types and functions > cell types and functions > cell types > B cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > B cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > B cells bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription |
| CSHL Authors: | |
| Communities: | CSHL labs > Amor lab |
| Depositing User: | Sasha Luks-Morgan |
| Date: | 18 December 2014 |
| Date Deposited: | 17 Sep 2021 20:16 |
| Last Modified: | 17 Sep 2021 20:16 |
| PMCID: | PMC4322776 |
| URI: | https://repository.cshl.edu/id/eprint/40355 |
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