2. Academic Validation
  3. Transcription-coupled AID deamination damage depends on ELOF1-associated RNA polymerase II

Transcription-coupled AID deamination damage depends on ELOF1-associated RNA polymerase II

  • Mol Cell. 2025 Feb 26:S1097-2765(25)00111-X. doi: 10.1016/j.molcel.2025.02.006.
Pengfei Dai 1,  Yuanqing Tan 2,  Yifeng Luo 3,  Tingting Liu 3,  Yanchao Huang 2,  Yafang Shang 4,  Min Emma Huang 4,  Xiaojing Liu 3,  Senxin Zhang 5,  Yanyan Wang 6,  Qian-Xi Li 3,  Niu Li 7,  Lulu Li 7,  Yining Qin 3,  Junqi Liu 3,  Liu Daisy Liu 3,  Xia Xie 3,  Yanni Cai 3,  Fei Xavier Chen 8,  Xiaoqi Zheng 9,  Leng-Siew Yeap 6,  Jian Wang 10,  Jinchuan Hu 11,  Fei-Long Meng 12
Affiliations

Affiliations

  • 1 International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Embryo Original Diseases, Shanghai 200030, China; Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Academy of Natural Sciences (SANS), Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 2 Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
  • 3 Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Academy of Natural Sciences (SANS), Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 4 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 310024, China.
  • 5 Shanghai Institute of Department of Mathematics, Shanghai Normal University, Shanghai 200234, China.
  • 6 Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 7 International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Embryo Original Diseases, Shanghai 200030, China.
  • 8 Fudan University Shanghai Cancer Center, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China.
  • 9 Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 10 International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Embryo Original Diseases, Shanghai 200030, China. Electronic address: labwangjian@shsmu.edu.cn.
  • 11 Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: hujinchuan@fudan.edu.cn.
  • 12 Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Academy of Natural Sciences (SANS), Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; 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 310024, China. Electronic address: feilong.meng@sibcb.ac.cn.
PMID: 40049162 DOI: 10.1016/j.molcel.2025.02.006
Abstract

In adaptive immunity, transcription-coupled damage (TCD) is introduced into antibody genes by activation-induced cytidine deaminase (AID) to diversify antibody repertoire. However, the coordination between transcription and DNA damage/repair remains elusive. Here, we find that transcription elongation factor 1 (ELOF1) stabilizes paused RNA polymerase II (RNAPII) at transcription barriers, providing a platform for transcription-coupled DNA damage/repair. Using a genetic screen, we discover that ELOF1 is required for AID targeting and that ELOF1 deficiency results in defective antibody class switch recombination and somatic hypermutation in mice. While downstream transcription-coupled repair factors are dispensable for AID damage, ELOF1 mechanistically facilitates both TCD and repair by stabilizing chromatin-bound RNAPII. In ELOF1-deficient cells, paused RNAPII tends to detach from chromatin and fails to recruit factors to induce or repair DNA damage. Our study places ELOF1 at the center of transcription-coupled DNA metabolism processes and suggests a transition of RNAPII from elongation to a DNA damage/repair scaffold.

Keywords

AID; ELOF1; class switch recombination; somatic hypermutation; transcription-coupled damage; transcription-coupled repair.

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