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

Autor: Cheng, Hui-Ching, Huang, Po-Hsien, Lai, Feng-Jie, Jan, Ming-Shiou, Chen, Yi-Lin, Chen, Szu-Ying, Chen, Wan-Li, Hsu, Chao-Kai, Huang, Wenya, Hsu, Li-Jin
Zdroj: Cellular & Molecular Life Sciences; Nov2023, Vol. 80 Issue 11, p1-18, 18p
Abstrakt: 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 p16Ink4a 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 p21Cip1/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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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