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

Hekang Du; Nanyang Xiao; Sitong Zhang; Xueyuan Zhou; Yangfan Zhang; Zengzeng Lu; Yuqian Fu; Miaohui Huang; Shan Xu; Qi Chen

doi:10.1016/j.isci.2023.107090

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. eCollection 2023 Jul 21.

Authors

Hekang Du¹, Nanyang Xiao^{1

2}, Sitong Zhang¹, Xueyuan Zhou¹, Yangfan Zhang¹, Zengzeng Lu¹, Yuqian Fu¹, Miaohui Huang¹, Shan Xu¹, Qi Chen¹

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.

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.