title: Activation-induced cytidine deaminase-initiated off-target DNA breaks are detected and resolved during S phase.
abstract: 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 G₁ phase of the cell cycle, and are repaired via end joining, CSR is considered a predominantly G₁ 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-G₁ 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 G₁-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 G₁. These data suggest that AID-mediated DSBs can evade G₁/S checkpoint activation and persist beyond G₁, 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.
authors: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors: Muneer G
authors: MG
authors: Hasham
authors: Kathy J
authors: KJ
authors: Snow
authors: Nina M
authors: NM
authors: Donghia
authors: Jane A
authors: JA
authors: Branca
authors: Mark D
authors: MD
authors: Lessard
authors: Janet
authors: J
authors: Stavnezer
authors: Lindsay S
authors: LS
authors: Shopland
authors: Kevin D
authors: KD
authors: Mills
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics / Q000276:immunology; D016193:G1 Phase / Q000235:genetics / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007132:Immunoglobulin Isotypes / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016196:S Phase / Q000235:genetics* / Q000276:immunology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007132:Immunoglobulin Isotypes; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase