Abstract
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.
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Acknowledgements
This work was supported by the grants from the National Natural Science Foundation of China (grant numbers: 31771335, 31770825, 31571317, 20180101232JC, and 20140204003YY) and the Science and Technology Development Project of Jilin Province (grant numbers: 20180101232JC and 20180101234JC).
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Lin, C., Li, H., Liu, J. et al. Arginine hypomethylation-mediated proteasomal degradation of histone H4—an early biomarker of cellular senescence. Cell Death Differ 27, 2697–2709 (2020). https://doi.org/10.1038/s41418-020-0562-8
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DOI: https://doi.org/10.1038/s41418-020-0562-8
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