Volume 30, No 9, Sep 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 9, September 2020: 732-744

ORIGINAL ARTICLES

ERCC6L2 promotes DNA orientation-specific recombination in mammalian cells

Xiaojing Liu^1,2,† , Tingting Liu^1,2,† , Yafang Shang^1,2,† , Pengfei Dai^1,2,† , Wubing Zhang³ , Brian J. Lee⁴ , Min Huang^1,2 , Dingpeng Yang^1,2 , Qiu Wu³ , Liu Daisy Liu^1,2 , Xiaoqi Zheng⁵ , Bo O. Zhou^1,2 , Junchao Dong⁶ , Leng-Siew Yeap⁷ , Jiazhi Hu⁸ , Tengfei Xiao⁹ , Shan Zha⁴ , Rafael Casellas¹⁰ , X. Shirley Liu¹¹ , Fei-Long Meng^1,2,*

¹State 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;
²University of Chinese Academy of Sciences, Beijing 100049, China;
³Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China;
⁴Institute for Cancer Genetics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA;
⁵Department of Mathematics, Shanghai Normal University, Shanghai 200234, China;
⁶Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China;
⁷Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
⁸The 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;
⁹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA;
¹⁰Lymphocyte Nuclear Biology, NIAMS, Center of Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
¹¹Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H.Chan School of Public Health, Boston, MA 02215, USA
^†These authors contributed equally
Correspondence: Fei-Long Meng(Feilong.Meng@sibcb.ac.cn)

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.

https://doi.org/10.1038/s41422-020-0328-3

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