Loss of fragile WWOX gene leads to senescence escape and genome instability

Hui Ching Cheng, Po Hsien Huang, Feng Jie Lai, Ming Shiou Jan, Yi Lin Chen, Szu Ying Chen, Wan Li Chen, Chao Kai Hsu, Wenya Huang, Li Jin Hsu

研究成果: Article同行評審

1 引文 斯高帕斯(Scopus)

摘要

Induction of DNA damage response (DDR) to ensure accurate duplication of genetic information is crucial for maintaining genome integrity during DNA replication. Cellular senescence is a DDR mechanism that prevents the proliferation of cells with damaged DNA to avoid mitotic anomalies and inheritance of the damage over cell generations. Human WWOX gene resides within a common fragile site FRA16D that is preferentially prone to form breaks on metaphase chromosome upon replication stress. We report here that primary Wwox knockout (Wwox −/−) mouse embryonic fibroblasts (MEFs) and WWOX-knockdown human dermal fibroblasts failed to undergo replication-induced cellular senescence after multiple passages in vitro. Strikingly, by greater than 20 passages, accelerated cell cycle progression and increased apoptosis occurred in these late-passage Wwox −/− MEFs. These cells exhibited γH2AX upregulation and microsatellite instability, indicating massive accumulation of nuclear DNA lesions. Ultraviolet radiation-induced premature senescence was also blocked by WWOX knockdown in human HEK293T cells. Mechanistically, overproduction of cytosolic reactive oxygen species caused p16 Ink4a promoter hypermethylation, aberrant p53/p21Cip1/Waf1 signaling axis and accelerated p27Kip1 protein degradation, thereby leading to the failure of senescence induction in Wwox-deficient cells after serial passage in culture. We determined that significantly reduced protein stability or loss-of-function A135P/V213G mutations in the DNA-binding domain of p53 caused defective induction of p21 Cip1/Waf1 in late-passage Wwox −/− MEFs. Treatment of N-acetyl-l-cysteine prevented downregulation of cyclin-dependent kinase inhibitors and induced senescence in Wwox −/− MEFs. Our findings support an important role for fragile WWOX gene in inducing cellular senescence for maintaining genome integrity during DDR through alleviating oxidative stress.

原文English
文章編號338
期刊Cellular and Molecular Life Sciences
80
發行號11
DOIs
出版狀態Published - 2023 11月

All Science Journal Classification (ASJC) codes

  • 分子醫學
  • 分子生物學
  • 藥理
  • 細胞與分子神經科學
  • 細胞生物學

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