Journal
CELL
Volume 159, Issue 7, Pages 1538-1548Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.11.014
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Funding
- NIH grants [R01AI077595, P01CA109901]
- Leukemia and Lymphoma Society (LLS) SCOR grant
- NIH grant [1R01GM099409]
- Leukemia and Lymphoma Society SCOR
- National Science Foundation
- NIH [1R01 CA176745-01, P01 CA109901, AI072529, AI037526]
- intramural research program of NIAMS, NIH
- Robertson Foundation/Cancer Research Institute Irvington Fellowship
- National Science Foundation of China [NSFC 31329003]
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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.
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