TY - JOUR
T1 - The cell cycle restricts activation-induced cytidine deaminase activity to early G1
AU - Wang, Qiao
AU - Kieffer-Kwon, Kyong Rim
AU - Oliveira, Thiago Y.
AU - Mayer, Christian T.
AU - Yao, Kaihui
AU - Pai, Joy
AU - Cao, Zhen
AU - Dose, Marei
AU - Casellas, Rafael
AU - Jankovic, Mila
AU - Nussenzweig, Michel C.
AU - Robbiani, Davide F.
N1 - Publisher Copyright:
© 2017 Wang et al.
PY - 2017
Y1 - 2017
N2 - 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 offtarget 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.
AB - 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 offtarget 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.
UR - http://www.scopus.com/inward/record.url?scp=85008506334&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85008506334&partnerID=8YFLogxK
U2 - 10.1084/jem.20161649
DO - 10.1084/jem.20161649
M3 - Article
C2 - 27998928
AN - SCOPUS:85008506334
SN - 0022-1007
VL - 214
SP - 49
EP - 58
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -