Metabolic regulation by p53 prevents R-loop-associated genomic instability

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2022
Autor:innen
Panatta, Emanuele
Mammarella, Eleonora
Pitolli, Consuelo
Mauriello, Alessandro
Knight, Richard A.
Melino, Gerry
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Cell Reports. Cell Press. 2022, 41(5), 111568. eISSN 2211-1247. Available under: doi: 10.1016/j.celrep.2022.111568
Zusammenfassung

Gene-environment interactions can perturb the epigenome, triggering network alterations that participate in cancer pathogenesis. Integrating epigenomics, transcriptomics, and metabolic analyses with functional perturbation, we show that the tumor suppressor p53 preserves genomic integrity by empowering adequate levels of the universal methyl donor S-adenosylmethionine (SAM). In p53-deficient cells, perturbation of DNA methylation promotes derepression of heterochromatin, massive loss of histone H3-lysine 9 methylation, and consequent upregulation of satellite RNAs that triggers R-loop-associated replication stress and chromosomal aberrations. In p53-deficient cells, the inadequate SAM level underlies the inability to respond to perturbation because exogenous reintroduction of SAM represses satellite elements and restores the ability to cope with stress. Mechanistically, p53 transcriptionally controls genes involved in one-carbon metabolism, including Slc43a2, the methionine uptake transporter that is critical for SAM synthesis. Supported by clinical data, our findings shed light on the role of p53-mediated metabolism in preventing unscheduled R-loop-associated genomic instability.

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
570 Biowissenschaften, Biologie
Schlagwörter
tumor suppression; p53; epigenetic integrity; chromosome stability; cancer
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ISO 690PANATTA, Emanuele, Alessio BUTERA, Eleonora MAMMARELLA, Consuelo PITOLLI, Alessandro MAURIELLO, Marcel LEIST, Richard A. KNIGHT, Gerry MELINO, Ivano AMELIO, 2022. Metabolic regulation by p53 prevents R-loop-associated genomic instability. In: Cell Reports. Cell Press. 2022, 41(5), 111568. eISSN 2211-1247. Available under: doi: 10.1016/j.celrep.2022.111568
BibTex
@article{Panatta2022-11-01Metab-59046,
  year={2022},
  doi={10.1016/j.celrep.2022.111568},
  title={Metabolic regulation by p53 prevents R-loop-associated genomic instability},
  number={5},
  volume={41},
  journal={Cell Reports},
  author={Panatta, Emanuele and Butera, Alessio and Mammarella, Eleonora and Pitolli, Consuelo and Mauriello, Alessandro and Leist, Marcel and Knight, Richard A. and Melino, Gerry and Amelio, Ivano},
  note={Article Number: 111568}
}
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