UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination

Liu, Jiang; Guan, Di; Dong, Maogong; Yang, Jingjing; Wei, Haibin; Liang, Qian; Song, Lijian; Xu, Lu; Bai, Junjie; Liu, Cui; Mao, Jian; Zhang, Qian; Zhou, Junzhi; Wu, Xiaoying; Wang, Miao; Cong, Yu‐Sheng

doi:10.1038/s41556-020-0559-z

Cited by 129 publications

(103 citation statements)

References 37 publications

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“…Recently, it was reported that UFM1 covalently modifies p53; this phenomenon is called UFMylation [57]. UFMylated p53 is stabilized at the protein level, as this covalent modification antagonizes p53 ubiquitination and proteasomal degradation.…”

Section: Resultsmentioning

confidence: 99%

The Changes in the p53 Protein across the Animal Kingdom Point to Its Involvement in Longevity

Bartas

Brázda

Volná

et al. 2021

IJMS

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Recently, the quest for the mythical fountain of youth has produced extensive research programs that aim to extend the healthy lifespan of humans. Despite advances in our understanding of the aging process, the surprisingly extended lifespan and cancer resistance of some animal species remain unexplained. The p53 protein plays a crucial role in tumor suppression, tissue homeostasis, and aging. Long-lived, cancer-free African elephants have 20 copies of the TP53 gene, including 19 retrogenes (38 alleles), which are partially active, whereas humans possess only one copy of TP53 and have an estimated cancer mortality rate of 11–25%. The mechanism through which p53 contributes to the resolution of the Peto’s paradox in Animalia remains vague. Thus, in this work, we took advantage of the available datasets and inspected the p53 amino acid sequence of phylogenetically related organisms that show variations in their lifespans. We discovered new correlations between specific amino acid deviations in p53 and the lifespans across different animal species. We found that species with extended lifespans have certain characteristic amino acid substitutions in the p53 DNA-binding domain that alter its function, as depicted from the Phenotypic Annotation of p53 Mutations, using the PROVEAN tool or SWISS-MODEL workflow. In addition, the loop 2 region of the human p53 DNA-binding domain was identified as the longest region that was associated with longevity. The 3D model revealed variations in the loop 2 structure in long-lived species when compared with human p53. Our findings show a direct association between specific amino acid residues in p53 protein, changes in p53 functionality, and the extended animal lifespan, and further highlight the importance of p53 protein in aging.

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Section: Resultsmentioning

confidence: 99%

The Changes in the p53 Protein across the Animal Kingdom Point to Its Involvement in Longevity

Bartas

Brázda

Volná

et al. 2021

IJMS

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“…UBA5 mutations within the R2 sequence (A371T and it phosphomimicking variant A371E) did not affect significantly the formation of the UFC1~UFM1 conjugate ( Supplementary Figure S1C ), indicating that the mutation becomes important for downstream events in the ufmylation cascade—potentially during binding of UBA5 to the membrane-associated E3 ligase (UFL1), to targets (UFBP1 [ 12 ], ASC1 [ 16 ], p53 [ 17 ], etc.) or important for other regulatory events.…”

Section: Resultsmentioning

confidence: 99%

“…Since then, discovery of new targets for UFM1 and the characterization of functional consequences of their ufmylation has constantly increased. Recently, new ufmylation targets involved in cancer progression [ 16 , 17 ], DNA damage response [ 18 , 19 ], translation machinery [ 20 ] and ribosome functioning [ 13 , 14 ] have been identified. Taking in account the broad range of biological pathways affected by ufmylation, it is not surprising that impaired ufmylation can be connected to many human diseases [ 16 , 21 , 22 , 23 , 24 ] and seems to be essential for embryonic development [ 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

A Concerted Action of UBA5 C-Terminal Unstructured Regions Is Important for Transfer of Activated UFM1 to UFC1

Wesch

Löhr

Rogova

et al. 2021

IJMS

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Ubiquitin fold modifier 1 (UFM1) is a member of the ubiquitin-like protein family. UFM1 undergoes a cascade of enzymatic reactions including activation by UBA5 (E1), transfer to UFC1 (E2) and selective conjugation to a number of target proteins via UFL1 (E3) enzymes. Despite the importance of ufmylation in a variety of cellular processes and its role in the pathogenicity of many human diseases, the molecular mechanisms of the ufmylation cascade remains unclear. In this study we focused on the biophysical and biochemical characterization of the interaction between UBA5 and UFC1. We explored the hypothesis that the unstructured C-terminal region of UBA5 serves as a regulatory region, controlling cellular localization of the elements of the ufmylation cascade and effective interaction between them. We found that the last 20 residues in UBA5 are pivotal for binding to UFC1 and can accelerate the transfer of UFM1 to UFC1. We solved the structure of a complex of UFC1 and a peptide spanning the last 20 residues of UBA5 by NMR spectroscopy. This structure in combination with additional NMR titration and isothermal titration calorimetry experiments revealed the mechanism of interaction and confirmed the importance of the C-terminal unstructured region in UBA5 for the ufmylation cascade.

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“…Recently, it has been reported that UFM1 covalently modifies p53 and this phenomenon is called UFMylation [57]. UFMylated p53 is stabilized on the protein level as this colavalent modification antagonizes p53 ubiquitination and proteasomal degradation.…”

Section: Resultsmentioning

confidence: 99%

The changes in the p53 protein across the animal kingdom pointing to its involvement in longevity

Bartas

Volná

Zawacka-Pankau

et al. 2020

Preprint

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Recently, the quest for the mythical fountain of youth has turned into specific research programs aiming to extend the healthy lifespan of humans. Despite advances in our understanding of the molecular processes underlying aging, the surprisingly extended lifespan of some animals remains unexplained. In this respect, the p53 protein plays a crucial role not only in tumor suppression but also in tissue homeostasis and healthy aging. However, the mechanism through which p53 maintains the function as a gatekeeper of healthy aging is not fully understood. Thus, we inspected TP53 gene sequences in individual species of phylogenetically related organisms that show different aging patterns. We discovered novel correlations between specific amino acid variations in p53 and lifespan across different animal species. In particular, we found that species with extended lifespan have characteristic amino acid substitutions mainly in the p53 DNA binding domain that change its function. Our findings show a direct association of specific amino acid residues in p53 protein with extended organismal lifespan and the importance of p53 protein in aging.

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UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination

Cited by 129 publications

References 37 publications

The Changes in the p53 Protein across the Animal Kingdom Point to Its Involvement in Longevity

The Changes in the p53 Protein across the Animal Kingdom Point to Its Involvement in Longevity

A Concerted Action of UBA5 C-Terminal Unstructured Regions Is Important for Transfer of Activated UFM1 to UFC1

The changes in the p53 protein across the animal kingdom pointing to its involvement in longevity

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