Resveratrol blocks retrotransposition of LINE-1 through PPAR α and sirtuin-6.
Resveratrol blocks retrotransposition of LINE-1 through PPAR α and sirtuin-6.
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DOI：
10.1038/s41598-022-11761-0
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发表时间：
2022-05-11
影响因子：
4.6
通讯作者：
Tamamori-Adachi, Mimi
中科院分区：
文献类型：
--
作者：
Okudaira, Noriyuki;Ishizaka, Yukihito;Tamamori-Adachi, Mimi
逆转录因子长散布因子-1（LINE-1或L1）占人类基因组的约17%。已知L1反转录转座会导致基因组不稳定和相关疾病，白藜芦醇抑制这种反转录转座;然而，其潜在机制仍不清楚。最近的观察表明，低分子量化合物可能通过未知的机制诱导L1反转录转座。研究多酚类物质白藜芦醇（RV）对体细胞L1-RTP（反转录转座）的影响。令人惊讶的是，RV完全阻断L1-RTP。利用PPARα抑制剂GW 6471或siRNA介导的PPARα耗竭实验表明，RV介导的L1-RTP抑制依赖于过氧化物酶体增殖物激活受体α（PPARα）。我们证明，RV抑制p38和cAMP反应元件结合蛋白磷酸化，这是参与MAPK信号，和L1-ORF 1蛋白的染色质募集。此外，RV增加sirtuin-6（SIRT 6）的表达，从而抑制L1的激活。sirtuins家族，SIRT 1，SIRT 6和SIRT 7，而不是SIRT 3，参与RV介导的L1-RTP抑制。总之，我们的研究结果表明，RV直接调节体细胞中PPARα介导的L1-RTP，MAPK信号与SIRT 6密切相互作用，可能在预防人类疾病如癌症中发挥作用。
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.
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DOI：
10.1073/pnas.1416869112
发表时间：
2015-04-07
影响因子：
11.1
作者：
Cook, Pamela R.;Jones, Charles E.;Furano, Anthony V.
通讯作者：
Furano, Anthony V.
影响因子：
64.5
作者：
Gilbert, N;Lutz-Prigge, S;Moran, JV
通讯作者：
Moran, JV
影响因子：
7.7
作者：
Mita P;Wudzinska A;Sun X;Andrade J;Nayak S;Kahler DJ;Badri S;LaCava J;Ueberheide B;Yun CY;Fenyö D;Boeke JD
通讯作者：
Boeke JD
影响因子：
25
作者：
Li, Wanhe;Prazak, Lisa;Chatterjee, Nabanita;Grueninger, Servan;Krug, Lisa;Theodorou, Delphine;Dubnau, Josh
通讯作者：
Dubnau, Josh
影响因子：
5.5
作者：
Ariumi Y
通讯作者：
Ariumi Y