Activation-induced cytidine deaminase-initiated off-target DNA breaks are detected and resolved during S phase
Authors
Hasham, Muneer G.Snow, Kathy J.
Donghia, Nina M.
Branca, Jane A.
Lessard, Mark D.
Stavnezer, Janet
Shopland, Lindsay S.
Mills, Kevin D.
UMass Chan Affiliations
Department of Cell BiologyDepartment of Microbiology and Physiological Systems
Document Type
Journal ArticlePublication Date
2012-09-01Keywords
AnimalsB-Lymphocytes
Cells, Cultured
Cytidine Deaminase
*DNA Breaks, Double-Stranded
DNA Repair
G1 Phase
Immunoglobulin Class Switching
Immunoglobulin Isotypes
Mice
Mice, Inbred C57BL
Mice, Knockout
S Phase
Genetics and Genomics
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
Activation-induced cytidine deaminase (AID) initiates DNA double-strand breaks (DSBs) in the IgH gene (Igh) to stimulate isotype class switch recombination (CSR), and widespread breaks in non-Igh (off-target) loci throughout the genome. Because the DSBs that initiate class switching occur during the G(1) phase of the cell cycle, and are repaired via end joining, CSR is considered a predominantly G(1) reaction. By contrast, AID-induced non-Igh DSBs are repaired by homologous recombination. Although little is known about the connection between the cell cycle and either induction or resolution of AID-mediated non-Igh DSBs, their repair by homologous recombination implicates post-G(1) phases. Coordination of DNA breakage and repair during the cell cycle is critical to promote normal class switching and prevent genomic instability. To understand how AID-mediated events are regulated through the cell cycle, we have investigated G(1)-to-S control in AID-dependent genome-wide DSBs. We find that AID-mediated off-target DSBs, like those induced in the Igh locus, are generated during G(1). These data suggest that AID-mediated DSBs can evade G(1)/S checkpoint activation and persist beyond G(1), becoming resolved during S phase. Interestingly, DSB resolution during S phase can promote not only non-Igh break repair, but also Ig CSR. Our results reveal novel cell cycle dynamics in response to AID-initiated DSBs, and suggest that the regulation of the repair of these DSBs through the cell cycle may ensure proper class switching while preventing AID-induced genomic instability.Source
J Immunol. 2012 Sep 1;189(5):2374-82. doi: 10.4049/jimmunol.1200414. Link to article on publisher's site
DOI
10.4049/jimmunol.1200414Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36455PubMed ID
22826323Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.1200414