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J Exp Med. 2017 Jan;214(1):49-58. doi: 10.1084/jem.20161649. Epub 2016 Dec 20.

The cell cycle restricts activation-induced cytidine deaminase activity to early G1.

Author information

1
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 qiaoqiaolang@gmail.com nussen@rockefeller.edu drobbiani@rockefeller.edu.
2
Genomics and Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.
3
Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
4
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
5
Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
6
Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065.

Abstract

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.

PMID:
27998928
PMCID:
PMC5206505
DOI:
10.1084/jem.20161649
[Indexed for MEDLINE]
Free PMC Article

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