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Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response
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 TREX...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320204/ https://www.ncbi.nlm.nih.gov/pubmed/37416470 http://dx.doi.org/10.1016/j.isci.2023.107090 |
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author | Du, Hekang Xiao, Nanyang Zhang, Sitong Zhou, Xueyuan Zhang, Yangfan Lu, Zengzeng Fu, Yuqian Huang, Miaohui Xu, Shan Chen, Qi |
author_facet | Du, Hekang Xiao, Nanyang Zhang, Sitong Zhou, Xueyuan Zhang, Yangfan Lu, Zengzeng Fu, Yuqian Huang, Miaohui Xu, Shan Chen, Qi |
author_sort | Du, Hekang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10320204 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-103202042023-07-06 Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response Du, Hekang Xiao, Nanyang Zhang, Sitong Zhou, Xueyuan Zhang, Yangfan Lu, Zengzeng Fu, Yuqian Huang, Miaohui Xu, Shan Chen, Qi iScience Article 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. Elsevier 2023-06-10 /pmc/articles/PMC10320204/ /pubmed/37416470 http://dx.doi.org/10.1016/j.isci.2023.107090 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Du, Hekang Xiao, Nanyang Zhang, Sitong Zhou, Xueyuan Zhang, Yangfan Lu, Zengzeng Fu, Yuqian Huang, Miaohui Xu, Shan Chen, Qi Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response |
title | Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response |
title_full | Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response |
title_fullStr | Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response |
title_full_unstemmed | Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response |
title_short | Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response |
title_sort | suppression of trex1 deficiency-induced cellular senescence and interferonopathies by inhibition of dna damage response |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320204/ https://www.ncbi.nlm.nih.gov/pubmed/37416470 http://dx.doi.org/10.1016/j.isci.2023.107090 |
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