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Deciphering the acetylation code of p53 in transcription regulation and tumor suppression

Abstract

Although it is well-established that p53-mediated tumor suppression mainly acts through its ability in transcriptional regulation, the molecular mechanisms of this regulation are not completely understood. Among a number of regulatory modes, acetylation of p53 attracts great interests. p53 was one of the first non-histone proteins found to be functionally regulated by acetylation and deacetylation, and subsequent work has established that reversible acetylation is a general mechanism for regulation of non-histone proteins. Unlike other types of posttranslational modifications occurred during stress responses, the role of p53 acetylation has been recently validated in vivo by using the knock-in mice with both acetylation-defective and acetylation-mimicking p53 mutants. Here, we review the role of acetylation in p53-mediated activities, with a focus on which specific acetylation sites are critical for p53-dependent transcription regulation during tumor suppression and how acetylation of p53 recruits specific “readers” to execute its promoter-specific regulation of different targets. We also discuss the role of p53 acetylation in differentially regulating its classic activities in cell cycle arrest, senescence and apoptosis as well as newly identified unconventional functions such as cell metabolism and ferroptosis.

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Fig. 1: Overview of p53 acetylation sites and enzymes involved.
Fig. 2: Functional significance of p53 acetylation underlined by mouse models.
Fig. 3: Graphical presentation of acetylation-mediated regulation of p53 tumor suppressive functions, as revealed in mouse models.
Fig. 4: Distinct functional consequences of p53 acetylation in DBD and CTD.
Fig. 5: Molecular readers for p53 acetylation.

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Acknowledgements

This work was supported by the National Cancer Institute of the National Institutes of Health under Award R35CA253059, RO1CA258390 and R01CA254970 to WG. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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ZX wrote and edited the manuscript and prepared the figures. NK, APG and OT proofread and edited the manuscript and the figures. WG conceived and edited the manuscript. All authors approved the final version.

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Correspondence to Wei Gu.

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OT is currently an employee of AstraZeneca and has stock ownership in AstraZeneca. All other authors declare that they have no conflict of interest.

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Xia, Z., Kon, N., Gu, A.P. et al. Deciphering the acetylation code of p53 in transcription regulation and tumor suppression. Oncogene 41, 3039–3050 (2022). https://doi.org/10.1038/s41388-022-02331-9

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