Your browser doesn't support javascript.
loading
C-to-G editing generates double-strand breaks causing deletion, transversion and translocation.
Huang, Min Emma; Qin, Yining; Shang, Yafang; Hao, Qian; Zhan, Chuanzong; Lian, Chaoyang; Luo, Simin; Liu, Liu Daisy; Zhang, Senxin; Zhang, Yu; Wo, Yang; Li, Niu; Wu, Shuheng; Gui, Tuantuan; Wang, Binbin; Luo, Yifeng; Cai, Yanni; Liu, Xiaojing; Xu, Ziye; Dai, Pengfei; Li, Simiao; Zhang, Liang; Dong, Junchao; Wang, Jian; Zheng, Xiaoqi; Xu, Yingjie; Sun, Yihua; Wu, Wei; Yeap, Leng-Siew; Meng, Fei-Long.
Afiliação
  • Huang ME; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
  • Qin Y; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesUniversity of Chinese Academy of Sciences, Shanghai, China.
  • Shang Y; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesUniversity of Chinese Academy of Sciences, Shanghai, China.
  • Hao Q; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
  • Zhan C; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesUniversity of Chinese Academy of Sciences, Shanghai, China.
  • Lian C; Department of Immunology and Microbiology, Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Luo S; Department of Endocrinology and Metabolic Diseases, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Liu LD; Department of Immunology and Microbiology, Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zhang S; Department of Endocrinology and Metabolic Diseases, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zhang Y; Department of Immunology and Microbiology, Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Wo Y; Department of Immunology and Microbiology, Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Li N; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesUniversity of Chinese Academy of Sciences, Shanghai, China.
  • Wu S; Department of Mathematics, Shanghai Normal University, Shanghai, China.
  • Gui T; Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Wang B; Departments of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Institute of Thoracic Oncology, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • Luo Y; Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Cai Y; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesUniversity of Chinese Academy of Sciences, Shanghai, China.
  • Liu X; Department of Immunology and Microbiology, Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Xu Z; Department of Immunology and Microbiology, Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Dai P; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesUniversity of Chinese Academy of Sciences, Shanghai, China.
  • Li S; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesUniversity of Chinese Academy of Sciences, Shanghai, China.
  • Zhang L; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesUniversity of Chinese Academy of Sciences, Shanghai, China.
  • Dong J; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesUniversity of Chinese Academy of Sciences, Shanghai, China.
  • Wang J; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesUniversity of Chinese Academy of Sciences, Shanghai, China.
  • Zheng X; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesUniversity of Chinese Academy of Sciences, Shanghai, China.
  • Xu Y; Hefei National Research Center for Cross Disciplinary Science, Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • Sun Y; Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • Wu W; International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Yeap LS; Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Meng FL; Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Cell Biol ; 26(2): 294-304, 2024 Feb.
Article em En | MEDLINE | ID: mdl-38263276
ABSTRACT
Base editors (BEs) introduce base substitutions without double-strand DNA cleavage. Besides precise substitutions, BEs generate low-frequency 'stochastic' byproducts through unclear mechanisms. Here, we performed in-depth outcome profiling and genetic dissection, revealing that C-to-G BEs (CGBEs) generate substantial amounts of intermediate double-strand breaks (DSBs), which are at the centre of several byproducts. Imperfect DSB end-joining leads to small deletions via end-resection, templated insertions or aberrant transversions during end fill-in. Chromosomal translocations were detected between the editing target and off-targets of Cas9/deaminase origin. Genetic screenings of DNA repair factors disclosed a central role of abasic site processing in DSB formation. Shielding of abasic sites by the suicide enzyme HMCES reduced CGBE-initiated DSBs, providing an effective way to minimize DSB-triggered events without affecting substitutions. This work demonstrates that CGBEs can initiate deleterious intermediate DSBs and therefore require careful consideration for therapeutic applications, and that HMCES-aided CGBEs hold promise as safer tools.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Translocação Genética / Ácidos Alcanossulfônicos / Quebras de DNA de Cadeia Dupla Limite: Humans Idioma: En Revista: Nat Cell Biol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Translocação Genética / Ácidos Alcanossulfônicos / Quebras de DNA de Cadeia Dupla Limite: Humans Idioma: En Revista: Nat Cell Biol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China