2. Academic Validation
  3. Sensing of DNA double-strand breaks by the NHEJ system stabilizes RORγt transcriptional activity and shapes Th17 pathogenicity in autoimmunity

Sensing of DNA double-strand breaks by the NHEJ system stabilizes RORγt transcriptional activity and shapes Th17 pathogenicity in autoimmunity

  • Cell Res. 2026 Jan 7. doi: 10.1038/s41422-025-01204-6.
Guan-Yu Chen # 1,  Wen-Jie Zhu # 1,  Zhuang Li # 1,  Yun-Wei Hu # 1 2,  Xiao-Shuang Luo # 1,  Zhi-Qing Mai 1,  Yuan Pan 1,  Yu-Xun Shi 1,  Zuo-Yi Li 1,  Jun Huang 1 2,  Pei-Dong Yuan 1 3,  Zhi-Qiang Xiao 1,  Qian Chen 1 4,  Yan-Yan Xie 1,  Hai-Xiang Huang 1,  Yu-Xi Chen 1,  Yao Lu 1 5,  Min-Zhen Wang 1,  Yi-Wen Xia 1,  Xiao-Qing Chen 6,  Dong-Ming Kuang 7,  Dan Liang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China.
  • 2 Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
  • 3 Department of Ophthalmology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
  • 4 Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 5 Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China. [email protected].
  • 7 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • 8 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 41495483 DOI: 10.1038/s41422-025-01204-6
Abstract

Robust mitochondrial ROS production induces extensive double-strand breaks (DSBs) in telomeric DNA of effector T cells, where the DNA repair machinery is rapidly hyper-evoked to sense and ligate DSBs during the respiratory burst. However, whether effector T cells can exploit the DNA repair system to simultaneously potentiate their functional activation remains largely unknown, especially in the context of autoimmunity. Here, we demonstrate that non-homologous end joining (NHEJ), a predominant mechanism of DNA repair, is highly activated in pathogenic T helper 17 (pTh17) cells and exerts a previously unrecognized effect on shaping the pathogenic nature of pTh17s to trigger autoimmunity. Mechanistically, the perception of DSBs by KU proteins facilitates auto-phosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which stabilizes RORγt to bind to the promoters of effector-gene loci, thus initiating the pTh17 effector program to induce autoimmunity. Using mass spectrometry and transcriptome analyses, we identified IER2 as a novel NHEJ factor that potentiates DNA-PKcs kinase activity in response to IL-23R stimulation, which is necessary for shaping Th17 pathogenicity. Therefore, targeting the immuno-pattern of the NHEJ system shows potential for the treatment of autoimmune diseases.

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