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


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.

SUBMITTER: Du H 

PROVIDER: S-EPMC10320204 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Suppression of <i>TREX1</i> deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response.

Du Hekang H   Xiao Nanyang N   Zhang Sitong S   Zhou Xueyuan X   Zhang Yangfan Y   Lu Zengzeng Z   Fu Yuqian Y   Huang Miaohui M   Xu Shan S   Chen Qi Q  

iScience 20230610 7


TREX1 encodes a major DNA exonuclease and mutations of this gene are associated with type I interferonopathies in human. Mice with <i>Trex1</i> deletion or mutation have shortened life spans accompanied by a senescence-associated secretory phenotype. However, the contribution of cellular senescence in <i>TREX1</i> deficiency-induced type I interferonopathies remains unknown. We found that features of cellular senescence present in <i>Trex1</i><sup><i>-/-</i></sup> mice are induced by multiple fa  ...[more]

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