Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 214, Issue 1, Pages 49-58Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20161649
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Funding
- National Institutes of Health [AI112602, AI037526, AI072529]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R37AI037526, R01AI072529, R01AI037526, R21AI112602] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [ZIAAR041148] Funding Source: NIH RePORTER
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Activation-induced cytidine deaminase (AID) converts cytosine into uracil to initiate somatic hypermutation (SHM) and class switch recombination (CSR) of antibody genes. In addition, this enzyme produces DNA lesions at off-target sites that lead to mutations and chromosome translocations. However, AID is mostly cytoplasmic, and how and exactly when it accesses nuclear DNA remains enigmatic. Here, we show that AID is transiently in spatial contact with genomic DNA from the time the nuclear membrane breaks down in prometaphase until early G1, when it is actively exported into the cytoplasm. Consistent with this observation, the immunoglobulin (Igh) gene deamination as measured by uracil accumulation occurs primarily in early G1 after chromosomes decondense. Altering the timing of cell cycle-regulated AID nuclear residence increases DNA damage at off-target sites. Thus, the cell cycle-controlled breakdown and reassembly of the nuclear membrane and the restoration of transcription after mitosis constitute an essential time window for AID-induced deamination, and provide a novel DNA damage mechanism restricted to early G1.
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