Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching
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During B-cell development, RAG endonuclease cleaves immunoglobulin heavy chain (IgH) V, D, and J gene segments and orchestrates their fusion as deletional events that assemble a V(D)J exon in the same transcriptional orientation as adjacent Cμ constant region exons. In mice, six additional sets of constant region exons (CHs) lie 100-200 kilobases downstream in the same transcriptional orientation as V(D)J and Cμ exons. Long repetitive switch (S) regions precede Cμ and downstream CHs. In mature B cells, class switch recombination (CSR) generates different antibody classes by replacing Cμ with a downstream CH (ref. 2). Activation-induced cytidine deaminase (AID) initiates CSR by promoting deamination lesions within Sμ and a downstream acceptor S region; these lesions are converted into DNA double-strand breaks (DSBs) by general DNA repair factors. Productive CSR must occur in a deletional orientation by joining the upstream end of an Sμ DSB to the downstream end of an acceptor S-region DSB. However, the relative frequency of deletional to inversional CSR junctions has not been measured. Thus, whether orientation-specific joining is a programmed mechanistic feature of CSR as it is for V(D)J recombination and, if so, how this is achieved is unknown. To address this question, we adapt high-throughput genome-wide translocation sequencing into a highly sensitive DSB end-joining assay and apply it to endogenous AID-initiated S-region DSBs in mouse B cells. We show that CSR is programmed to occur in a productive deletional orientation and does so via an unprecedented mechanism that involves in cis Igh organizational features in combination with frequent S-region DSBs initiated by AID. We further implicate ATM-dependent DSB-response factors in enforcing this mechanism and provide an explanation of why CSR is so reliant on the 53BP1 DSB-response factor.
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CTCF- and cohesin-associated loops play essential roles in V(D)J recombination of the immunoglobulin heavy-chain in developing lymphocytes.
“CTCF- and cohesin-associated loops also play essential roles in V(D)J recombination of the immunoglobulin heavy-chain in developing lymphocytes.”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Dong et al., 2015
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- Authors
- Dong, J., Panchakshari, R. A., Zhang, T., Zhang, Y., Hu, J., Volpi, S. A., Meyers, R. M., Ho, Y.-J., Du, Z., Robbiani, D. F., Meng, F., Gostissa, M., Nussenzweig, M. C., Manis, J. P., & Alt, F. W.
- Affiliations
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Manis, John P.
- Alt, Frederick W.
- ORCID
- Venue
- Nature
- Published
- 2015-08-26
- Volume
- 525
- Issue
- 7567
- Pages
- 134-139
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4592165
- OpenAlex
- W1960323088
- Cited by
- 123
- References
- 40
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 10 · 2023: 4 · 2022: 8 · 2021: 14 · 2020: 13 · 2019: 12 · 2018: 9 · 2017: 14 · 2016: 17 · 2015: 2
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (T32HL066987)
- National Cancer Institute (R21CA133781, CA133781)
- National Institute of Allergy and Infectious Diseases (AI112602, AI077595, R37AI037526, R01AI037526, R01AI072529, R21AI088510, R21AI112602, AI072529, AI037526, R01AI077595, R37AI077595)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- class switch recombination, activation-induced cytidine deaminase, immunoglobulin heavy chain locus, switch regions, DNA double-strand break repair, 53BP1, ATM, V(D)J recombination, B cell development, whole genome sequencing, antibody class switching
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, AICDA (Activation-Induced Cytidine Deaminase), Animals, B-Lymphocytes, Chromosomal Proteins, Non-Histone, Cytidine Deaminase, Deamination, DNA Repair, DNA-Binding Proteins, Immunoglobulin Constant Regions, Immunoglobulin Heavy Chains, Sequence Deletion, Immunoglobulin Class Switching, VDJ Exons, Mice, DNA Breaks, Double-Stranded, Ataxia Telangiectasia Mutated Proteins
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