Arginine hypomethylation-mediated proteasomal degradation of histone H4-an early biomarker of cellular senescence
Arginine hypomethylation-mediated proteasomal degradation of histone H4-an early biomarker of cellular senescence
复制标题
精氨酸低甲基化介导的组蛋白 H4 的蛋白酶体降解——细胞衰老的早期生物标志物
DOI：
10.1038/s41418-020-0562-8
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发表时间：
2020-05-23
影响因子：
12.4
通讯作者：
Zhang, Yu
中科院分区：
文献类型：
--
作者：
Lin, Cong;Li, Hongxin;Zhang, Yu
衰老伴随着组蛋白水平的改变，然而，组蛋白减少在细胞衰老中的作用和机制在很大程度上是未知的。蛋白质精氨酸甲基转移酶1（PRMT1）是生成单甲基和不对称二甲基精氨酸的主要酶。在这里，我们发现PRMT1介导的衰老的消除伴随着组蛋白H4水平的降低。在多种经典衰老模型下，H4的下降也先于其他3种核心组蛋白。值得注意的是，组蛋白H4在精氨酸3（H4R3me2as）的不对称去甲基化，由PRMT1催化，减少组蛋白H4之前。此外，我们发现PRMT1介导的H4R3me2as保持了H4的稳定性。H4R3me2as水平的降低增加了蛋白酶体激活剂PA200与组蛋白H4之间的相互作用，其催化H4的多聚泛素非依赖性降解。此外，H4降解促进核小体分解，导致衰老相关基因转录增加。值得注意的是，H4被3种众所周知的抗衰老药物（二甲双胍、雷帕霉素和白藜芦醇）恢复，比在H2O2诱导的衰老下检测到的其他衰老标志物早得多。因此，我们发现了H4R3me2as通过调节H4稳定性来调节细胞衰老的新功能。这一发现也指出了组蛋白H4作为衰老指标和潜在的抗衰老药物筛选标记物的价值。
Senescence is accompanied with histones level alteration; however, the roles and the mechanisms of histone reduction in cellular senescence are largely unknown. Protein arginine methyltransferase 1 (PRMT1) is the major enzyme that generates monomethyl and asymmetrical dimethyl arginine. Here we showed that abrogation of PRMT1-mediated senescence was accompanied with decreasing histone H4 level. Consistently, under multiple classic senescence models, H4 decreasing was also been found prior to the other 3 core histones. Noticeably, asymmetric demethylation of histone H4 at arginine 3 (H4R3me2as), catalyzed by PRMT1, was decreased prior to histone H4. In addition, we showed that the PRMT1-mediated H4R3me2as maintained H4 stability. Reduction of H4R3me2as level increased the interaction between proteasome activator PA200 and histone H4, which catalyzes the poly-ubiquitin-independent degradation of H4. Moreover, H4 degradation promoted nucleosome decomposition, resulting in increased senescence-associated genes transcription. Significantly, H4 was restored by 3 well-informed anti-aging drugs (metformin, rapamycin, and resveratrol) much earlier than other senescence markers detected under H2O2-induced senescence. Thus, we uncovered a novel function of H4R3me2as in modulation of cellular senescence via regulating H4 stability. This finding also points to the value of histone H4 as a senescence indicator and a potential anti-aging drug screening marker.