Abstract
The tumor suppressor p53 is an essential transcription factor that sensitively regulates cellular responses to various stresses. Acetylation, a critically important posttranslational modification of p53, is induced in response to cellular stresses. P53 acetylation level strongly correlates with protein stability and activity. The steady-state level of p53 acetylation is balanced by dynamic acetylation and deacetylation. Despite the function of p53 acetylation being well studied, how the steady state of p53 acetylation level is regulated in response to cellular stresses remains unclear. In particular, the dynamic regulation of the deacetylase activities responsible for p53 deacetylation during cellular stress is unknown. In the current study, we investigated the dynamic regulation of HDAC1 (histone deacetylase 1) and SIRT1 (sirtuin 1), two major enzymes for p53 deacetylation, during cell stress. We found that various cell stress events induce HDAC1 acetylation. The increased level of HDAC1 acetylation correlates with the level of p53 acetylation. Acetylated HDAC1 loses the ability to deacetylate p53. Cellular stresses also promote the decline of the SIRT1 protein in a proteasome-dependent pathway, which also results in the increase of p53 acetylation. Importantly, the decreased level of SIRT1 also contributes to the accumulation of HDAC1 acetylation as SIRT1 deacetylates HDAC1. Therefore, the increase of HDAC1 acetylation and reduced level of SIRT1 protein during cellular stress directly link to the induction of p53 acetylation. These results unveil the mechanism underlying the dynamic regulation of p53 acetylation during cell stress.
Highlights
We recently reported that HDAC1 can be acetylated after the induction of a transcription program.[11,13,14] Acetylated HDAC1 loses its own histone deacetylase activity and transrepresses the deacetylase activity of HDAC2.15 Interestingly, acetylated HDAC1 can be reversibly deacetylated by SIRT1.13 dynamic acetylation and deacetylation of HDAC1 can regulate HDAC1 deacetylase activity during cellular events
HDAC1 acetylation is induced under cellular stresses
Previous studies showed that HDAC1 acetylation modulates its deacetylase activity and can be induced during differentiation events and upon the induction of DNA double-strand break.[11,13,14,15]
Summary
We recently reported that HDAC1 can be acetylated after the induction of a transcription program.[11,13,14] Acetylated HDAC1 loses its own histone deacetylase activity and transrepresses the deacetylase activity of HDAC2.15 Interestingly, acetylated HDAC1 can be reversibly deacetylated by SIRT1.13 dynamic acetylation and deacetylation of HDAC1 can regulate HDAC1 deacetylase activity during cellular events. One of the first identified transcriptional targets of p53 is the cyclin-dependent kinase (CDK) inhibitor p21Waf1/Cip1.17 CDKs have an important role in regulating cell-cycle progression, and the inhibition of CDK activity by p21Waf1/Cip[1] results in a cell-cycle arrest.[18] The p53 protein level rises markedly within minutes of cellular stress treatment. This is achieved through posttranslational modifications of the p53 polypeptide, while there is no marked induction of p53 mRNA levels after DNA damage or other stress.[19,20] This provides a rapid, sensitive, flexible and readily reversible mechanism for p53 activity regulation in response to a number of different cellular stresses. These results unveil the mechanism underlying the regulation of p53 acetylation during cell stresses
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