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

Journal of Experimental Medicine - Tập 214 Số 1 - Trang 49-58 - 2017
Qiao Wang1, Kyong-Rim Kieffer-Kwon2,3, Thiago Y. Oliveira1, Christian T. Mayer1, Kai-Hui Yao1, Joy A. Pai1, Zhen Cao4, Marei Dose2,3, Rafael Casellas2,3, Mila Janković1, Michel C. Nussenzweig5,1, Davide F. Robbiani1
1Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, 10065 1
2Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 4
3Genomics and Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892 3
4Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center, New York, NY 10065 5
5Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065 2

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

Alt, 2013, Mechanisms of programmed DNA lesions and genomic instability in the immune system, Cell., 152, 417, 10.1016/j.cell.2013.01.007

Anderson, 2007, Nuclear envelope formation by chromatin-mediated reorganization of the endoplasmic reticulum, Nat. Cell Biol., 9, 1160, 10.1038/ncb1636

Casellas, 2016, Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity, Nat. Rev. Immunol., 16, 164, 10.1038/nri.2016.2

Chaudhuri, 2003, Transcription-targeted DNA deamination by the AID antibody diversification enzyme, Nature., 422, 726, 10.1038/nature01574

Crouch, 2007, Regulation of AID expression in the immune response, J. Exp. Med., 204, 1145, 10.1084/jem.20061952

Dickerson, 2003, AID mediates hypermutation by deaminating single stranded DNA, J. Exp. Med., 197, 1291, 10.1084/jem.20030481

Di Noia, 2007, Molecular mechanisms of antibody somatic hypermutation, Annu. Rev. Biochem., 76, 1, 10.1146/annurev.biochem.76.061705.090740

Doi, 2003, De novo protein synthesis is required for the activation-induced cytidine deaminase function in class-switch recombination, Proc. Natl. Acad. Sci. USA., 100, 2634, 10.1073/pnas.0437710100

Endres, 2004, Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase, J. Clin. Invest., 113, 1711, 10.1172/JCI200420926

Faili, 2002, AID-dependent somatic hypermutation occurs as a DNA single-strand event in the BL2 cell line, Nat. Immunol., 3, 815, 10.1038/ni826

Gaillard, 2015, Replication stress and cancer, Nat. Rev. Cancer., 15, 276, 10.1038/nrc3916

Gasnereau, 2007, Flow cytometry to sort mammalian cells in cytokinesis, Cytometry A., 71, 1, 10.1002/cyto.a.20352

Hagen, 2008, Cell cycle-specific UNG2 phosphorylations regulate protein turnover, activity and association with RPA, EMBO J., 27, 51, 10.1038/sj.emboj.7601958

Haug, 1998, Regulation of expression of nuclear and mitochondrial forms of human uracil-DNA glycosylase, Nucleic Acids Res., 26, 1449, 10.1093/nar/26.6.1449

Horváth, 2010, A one-step method for quantitative determination of uracil in DNA by real-time PCR, Nucleic Acids Res., 38, e196, 10.1093/nar/gkq815

Kaikkonen, 2013, Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription, Mol. Cell., 51, 310, 10.1016/j.molcel.2013.07.010

Lackey, 2012, APOBEC3B and AID have similar nuclear import mechanisms, J. Mol. Biol., 419, 301, 10.1016/j.jmb.2012.03.011

Lackey, 2013, Subcellular localization of the APOBEC3 proteins during mitosis and implications for genomic DNA deamination, Cell Cycle., 12, 762, 10.4161/cc.23713

Le, 2015, Cell Cycle Regulates Nuclear Stability of AID and Determines the Cellular Response to AID, PLoS Genet., 11, e1005411, 10.1371/journal.pgen.1005411

McBride, 2004, Somatic hypermutation is limited by CRM1-dependent nuclear export of activation-induced deaminase, J. Exp. Med., 199, 1235, 10.1084/jem.20040373

Meng, 2014, Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability, Cell., 159, 1538, 10.1016/j.cell.2014.11.014

Methot, 2015, Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm, J. Exp. Med., 212, 581, 10.1084/jem.20141157

Muramatsu, 2000, Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme, Cell., 102, 553, 10.1016/S0092-8674(00)00078-7

Patenaude, 2009, Active nuclear import and cytoplasmic retention of activation-induced deaminase, Nat. Struct. Mol. Biol., 16, 517, 10.1038/nsmb.1598

Pefanis, 2014, Noncoding RNA transcription targets AID to divergently transcribed loci in B cells, Nature., 514, 389, 10.1038/nature13580

Petersen, 2001, AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching, Nature., 414, 660, 10.1038/414660a

Qian, 2014, B cell super-enhancers recruit AID tumorigenic activity, Cell., 159, 1524, 10.1016/j.cell.2014.11.013

Robbiani, 2013, Chromosome translocation, B cell lymphoma, and activation-induced cytidine deaminase, Annu. Rev. Pathol., 8, 79, 10.1146/annurev-pathol-020712-164004

Robbiani, 2015, Plasmodium infection promotes genomic instability and AID-dependent B cell lymphoma, Cell., 162, 727, 10.1016/j.cell.2015.07.019

Sakaue-Sawano, 2008, Visualizing spatiotemporal dynamics of multicellular cell-cycle progression, Cell., 132, 487, 10.1016/j.cell.2007.12.033

Santaguida, 2015, Short- and long-term effects of chromosome mis-segregation and aneuploidy, Nat. Rev. Mol. Cell Biol., 16, 473, 10.1038/nrm4025

Victora, 2010, Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter, Cell., 143, 592, 10.1016/j.cell.2010.10.032

Wang, 2014, Epigenetic targeting of activation-induced cytidine deaminase, Proc. Natl. Acad. Sci. USA., 111, 18667, 10.1073/pnas.1420575111

Yeap, 2015, Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes, Cell., 163, 1124, 10.1016/j.cell.2015.10.042

Yu, 2003, R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells, Nat. Immunol., 4, 442, 10.1038/ni919

Zheng, 2015, Non-coding RNA Generated following Lariat Debranching Mediates Targeting of AID to DNA, Cell., 161, 762, 10.1016/j.cell.2015.03.020