TY - JOUR
T1 - Metabolic regulation by p53 prevents R-loop-associated genomic instability
AU - Panatta, Emanuele
AU - Butera, Alessio
AU - Mammarella, Eleonora
AU - Pitolli, Consuelo
AU - Mauriello, Alessandro
AU - Leist, Marcel
AU - Knight, Richard A.
AU - Melino, Gerry
AU - Amelio, Ivano
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - cancer
KW - chromosome stability
KW - tumor suppression
KW - epigenetic integrity
KW - p53
KW - CP: Molecular biology
KW - cancer
KW - chromosome stability
KW - tumor suppression
KW - epigenetic integrity
KW - p53
KW - CP: Molecular biology
UR - http://hdl.handle.net/10807/302922
U2 - 10.1016/j.celrep.2022.111568
DO - 10.1016/j.celrep.2022.111568
M3 - Article
SN - 2211-1247
VL - 41
SP - N/A-N/A
JO - Cell Reports
JF - Cell Reports
ER -