title: The cell cycle restricts activation-induced cytidine deaminase activity to early G1.
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.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 qiaoqiaolang@gmail.com nussen@rockefeller.edu drobbiani@rockefeller.edu.
authors.forename: Qiao
authors.identifier: 0000-0001-6416-1733
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Genomics and Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.|Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Kyong-Rim
authors.initials: KR
authors.lastname: Kieffer-Kwon
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Thiago Y
authors.identifier: 0000-0002-2654-0879
authors.initials: TY
authors.lastname: Oliveira
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Mayer
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Kaihui
authors.initials: K
authors.lastname: Yao
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Joy
authors.initials: J
authors.lastname: Pai
authors.affiliation: Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Genomics and Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.|Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Marei
authors.initials: M
authors.lastname: Dose
authors.affiliation: Genomics and Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.|Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Mila
authors.initials: M
authors.lastname: Jankovic
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 qiaoqiaolang@gmail.com nussen@rockefeller.edu drobbiani@rockefeller.edu.|Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065.
authors.forename: Michel C
authors.identifier: 0000-0003-0592-8564
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 qiaoqiaolang@gmail.com nussen@rockefeller.edu drobbiani@rockefeller.edu.
authors.forename: Davide F
authors.identifier: 0000-0001-7379-3484
authors.initials: DF
authors.lastname: Robbiani
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000378:metabolism*; D004249:DNA Damage; D003641:Deamination; D016193:G1 Phase; D005803:Genes, Immunoglobulin; D051379:Mice; D008810:Mice, Inbred C57BL; D014158:Transcription, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase