Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response

  • iScience. 2023 Jun 10;26(7):107090. doi: 10.1016/j.isci.2023.107090.
Hekang Du  1 ,  Nanyang Xiao  1  2 ,  Sitong Zhang  1 ,  Xueyuan Zhou  1 ,  Yangfan Zhang  1 ,  Zengzeng Lu  1 ,  Yuqian Fu  1 ,  Miaohui Huang  1 ,  Shan Xu  1 ,  Qi Chen  1
Affiliations
  • 1. Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University Qishan Campus, College Town, Fuzhou, Fujian Province 350117, China.
  • 2. Department of Microbiology, University of Chicago, Cummings Life Science Center, 920 East 58th Street, Chicago, IL 60637, USA.
PMID: 37416470 DOI: 10.1016/j.isci.2023.107090
Abstract

TREX1 encodes a major DNA exonuclease and mutations of this gene are associated with type I interferonopathies in human. Mice with Trex1 deletion or mutation have shortened life spans accompanied by a senescence-associated secretory phenotype. However, the contribution of cellular senescence in TREX1 deficiency-induced type I interferonopathies remains unknown. We found that features of cellular senescence present in Trex1-/- mice are induced by multiple factors, particularly DNA damage. The cGAS-STING and DNA damage response pathways are required for maintaining TREX1 deletion-induced cellular senescence. Inhibition of the DNA damage response, such as with Checkpoint kinase 2 (Chk2) inhibitor, partially alleviated progression of type I interferonopathies and lupus-like features in the mice. These data provide insights into the initiation and development of type I interferonopathies and lupus-like diseases, and may help inform the development of targeted therapeutics.

Keywords
Disease; Model organism; Molecular biology.
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