Resveratrol blocks retrotransposition of LINE-1 through PPAR α and sirtuin-6

• Published in: Scientific reports Vol. 12; no. 1; pp. 7772 - 14
• Main Authors: Okudaira, Noriyuki, Ishizaka, Yukihito, Tamamori-Adachi, Mimi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.05.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/45; 631/80; Cell cycle; Chromatin; Disease; Genes; Genomes; Genomic instability; Humanities and Social Sciences; Humans; Long Interspersed Nucleotide Elements; MAP kinase; Medical research; multidisciplinary; Peroxisome proliferator-activated receptors; Phosphorylation; PPAR alpha - genetics; Proteins; Resveratrol; Resveratrol - pharmacology; Retroelements; Retrotransposition; Science; Science (multidisciplinary); siRNA; SIRT1 protein; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Sirtuins; Sirtuins - genetics; Sirtuins - metabolism; Somatic cells
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-11761-0

The retroelement long interspersed element-1 ( LINE-1 or L1) comprises about 17% of the human genome. L1 retrotransposition is known to cause genomic instability and related disorders, and resveratrol suppresses this retrotransposition; however, the underlying mechanism is still not elucidated. Recent observations showed that low-molecular-weight compounds might induce L1 retrotransposition through unknown mechanisms. This study aimed to determine polyphenol resveratrol (RV)’s effect on L1-RTP (retrotransposition) in somatic cells. Surprisingly, RV completely blocked L1-RTP. Experiments using the PPARα inhibitor GW6471 or siRNA-mediated PPARα depletion showed that RV-mediated L1-RTP’s inhibition depended on peroxisome proliferator-activated receptor α (PPARα). We demonstrated that RV inhibits p38 and cAMP response element binding protein phosphorylation, which are involved in MAPK signaling, and the L1-ORF1 protein’s chromatin recruitment. Furthermore, RV increased the expression of sirtuin-6 (SIRT6), which inhibited the activation of L1. The sirtuins family, SIRT1, SIRT6, and SIRT7, but not SIRT3, are involved in RV-mediated inhibition of L1-RTP. Overall, our findings suggest that RV directly modulates PPARα-mediated L1-RTP in somatic cells and that MAPK signaling interacts with SIRT6 closely and may play a role in preventing human diseases such as cancer.