| Autor: |
Chen, Yu, Zhen, Zhengyi, Chen, Lingjiang, Wang, Hao, Wang, Xuhui, Sun, Xiaoxiang, Song, Zhiwei, Wang, Haiyan, Lin, Yizi, Zhang, Wenjun, Wu, Guizhu, Jiang, Ying, Mao, Zhiyong |
| Zdroj: |
EMBO Reports; 12/6/2023, Vol. 24 Issue 12, p1-15, 15p |
| Abstrakt: |
Aging is accompanied by a decreased DNA repair capacity, which might contribute to age‐associated functional decline in multiple tissues. Disruption in hormone signaling, associated with reproductive organ dysfunction, is an early event of age‐related tissue degeneration, but whether it impacts DNA repair in nonreproductive organs remains elusive. Using skin fibroblasts derived from healthy donors with a broad age range, we show here that the downregulation of expression of XRCC4, a factor involved in nonhomologous end‐joining (NHEJ) repair, which is the dominant pathway to repair somatic double‐strand breaks, is mediated through transcriptional mechanisms. We show that the androgen receptor (AR), whose expression is also reduced during aging, directly binds to and enhances the activity of the XRCC4 promoter, facilitating XRCC4 transcription and thus stabilizing the genome. We also demonstrate that dihydrotestosterone (DHT), a powerful AR agonist, restores XRCC4 expression and stabilizes the genome in different models of cellular aging. Moreover, DHT treatment reverses senescence‐associated phenotypes, opening a potential avenue to aging interventions in the future. Synopsis: Age‐related downregulation of the androgen receptor leads to decreased XRCC4 transcription, contributing to genome instability. Activation of androgen signaling increases XRCC4 expression to stabilize the genome and counteract senescence.In young individuals, relatively high levels of AR maintain an active transcription state of XRCC4, thereby promoting NHEJ repair and genomic stability.In aged individuals, reduced AR expression contributes to declined XRCC4 promoter activity, XRCC4 mRNA level, and NHEJ capacity, causing genomic instability and cellular senescence.Reactivation of androgen signaling with DHT rescues XRCC4 expression, reverses genomic instability and alleviates the onset of cellular senescence. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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