2. Academic Validation
  3. ERCC6L2 promotes DNA orientation-specific recombination in mammalian cells

ERCC6L2 promotes DNA orientation-specific recombination in mammalian cells

  • Cell Res. 2020 Sep;30(9):732-744. doi: 10.1038/s41422-020-0328-3.
Xiaojing Liu  # 1 2,  Tingting Liu  # 1 2,  Yafang Shang  # 1 2,  Pengfei Dai  # 1 2,  Wubing Zhang 3,  Brian J Lee 4,  Min Huang 1 2,  Dingpeng Yang 1 2,  Qiu Wu 3,  Liu Daisy Liu 1 2,  Xiaoqi Zheng 5,  Bo O Zhou 1 2,  Junchao Dong 6,  Leng-Siew Yeap 7,  Jiazhi Hu 8,  Tengfei Xiao 9,  Shan Zha 4,  Rafael Casellas 10,  X Shirley Liu  # 11,  Fei-Long Meng  # 12 13
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
  • 4 Institute for Cancer Genetics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
  • 5 Department of Mathematics, Shanghai Normal University, Shanghai, 200234, China.
  • 6 Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
  • 7 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 8 The MOE Key Laboratory of Cell Proliferation and Differentiation, Genome Editing Research Center, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, 100871, Beijing, China.
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
  • 10 Lymphocyte Nuclear Biology, NIAMS, Center of Cancer Research, NCI, NIH, Bethesda, MD, 20892, USA.
  • 11 Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H.Chan School of Public Health, Boston, MA, 02215, USA.
  • 12 State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. [email protected].
  • 13 University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • # Contributed equally.
PMID: 32355287 DOI: 10.1038/s41422-020-0328-3
Abstract

Programmed DNA recombination in mammalian cells occurs predominantly in a directional manner. While random DNA breaks are typically repaired both by deletion and by inversion at approximately equal proportions, V(D)J and class switch recombination (CSR) of immunoglobulin heavy chain gene overwhelmingly delete intervening sequences to yield productive rearrangement. What factors channel chromatin breaks to deletional CSR in lymphocytes is unknown. Integrating CRISPR knockout and chemical perturbation screening we here identify the Snf2-family helicase-like ERCC6L2 as one such factor. We show that ERCC6L2 promotes double-strand break end-joining and facilitates optimal CSR in mice. At the cellular levels, ERCC6L2 rapidly engages in DNA repair through its C-terminal domains. Mechanistically, ERCC6L2 interacts with other end-joining factors and plays a functionally redundant role with the XLF end-joining factor in V(D)J recombination. Strikingly, ERCC6L2 controls orientation-specific joining of broken ends during CSR, which relies on its helicase activity. Thus, ERCC6L2 facilitates programmed recombination through directional repair of distant breaks.

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