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

Panatta, Emanuele; Butera, Alessio; Mammarella, Eleonora; Pitolli, Consuelo; Mauriello, Alessandro; Leist, Marcel; Knight, Richard; Melino, Gerry; Amelio, Ivano

doi:10.1016/j.celrep.2022.111568

Cited by 19 publications

(4 citation statements)

References 45 publications

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“…S3F ). These data are consistent with reports that TP53 regulates DNA methylation 57–59 . Trim28 +/D9 hypomethylated DMLs were enriched almost exclusively in regions known to be targeted by TRIM28, with probe set enrichment analysis (PSEA) revealing annotations for heterochromatin , monoallelic methylation , Polycomb-silencing , CTCF , TRIM28-binding , and H3K9me3 ( Fig.…”

Section: Resultssupporting

confidence: 93%

Developmental priming of cancer susceptibility

Panzeri,

Fagnocchi,

Apostle

et al. 2023

Preprint

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DNA mutations are necessary drivers of cancer, yet only a small subset of mutated cells go on to cause the disease. To date, the mechanisms that determine which rare subset of cells transform and initiate tumorigenesis remain unclear. Here, we take advantage of a unique model of intrinsic developmental heterogeneity (Trim28+/D9) and demonstrate that stochastic early life epigenetic variation can trigger distinct cancer-susceptibility ′states′ in adulthood. We show that these developmentally primed states are characterized by differential methylation patterns at typically silenced heterochromatin, and that these epigenetic signatures are detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis. These results provide proof-of-concept that intrinsic developmental heterogeneity can prime individual, life-long cancer risk.

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Section: Resultssupporting

confidence: 93%

Developmental priming of cancer susceptibility

Panzeri,

Fagnocchi,

Apostle

et al. 2023

Preprint

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“…We recently showed that in PDAC-derived mouse cells p53 controls metabolic pathways by transcriptionally regulating a gene expression programme impinging on aminoacid metabolism [30]. Within this, regulation of methionine uptake appeared to affect the biosynthesis of S-adenosyl-methionine, a major methyl donor, altering the ability of the cell to cope with perturbation of DNA methylation and triggering genomic instability [6,17,30]. Thus, a link between epigenetic regulation of chromatin and metabolism emerged as underlying control mechanism of p53-mediated genomic integrity [27,49].…”

Section: Resultsmentioning

confidence: 99%

“…ATAC-seq and RNA-seq data come from [30] and are deposited under the following GEO accession numbers: GSE207878 (ATAC-seq) and GSE207879 (RNA-seq). Briefly, for ATAC-seq the cell pellet (KPsh ± doxy 48 h, 2 biological replicates) was resuspended in 500 µl of icecold cryopreservation solution (50% FBS, 40% growth media, 10% DMSO); for RNA-seq (KPCsh ± doxy 48 h, 3 biological replicates) the RNA was extracted using RNeasy Mini Kit (QIAGEN, #74106) followed by DNa-seI step (Sigma, #AMPD1-1KT); Active Motif performed sequencing and bioinformatic analysis.…”

Section: Atac-seq and Rna-seqmentioning

confidence: 99%

p53 regulates expression of nuclear envelope components in cancer cells

et al. 2022

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Nuclear organisation and architecture are essential for the maintenance of genomic integrity as well as for the epigenetic regulations and gene expression. Disruption of lamin B1, major structural and functional member of the nuclear lamina, is observed in human laminopathies and in sporadic cancers, and leads to chromosomal rearrangements and alterations of gene expression. The tumour suppressor p53 has been shown to direct specific transcriptional programmes by regulating lamin A/C, however its relationship with lamin B1 has remained elusive. Here, we show that loss of p53 correlates with increased expression of members belonging to the nuclear pore complex and nuclear lamina and directly regulates transcription of lamin B1. We show that the genomic loci of a fraction of p53-dependent genes physically interact with lamin B1 and Nup210. This observation provides a possible mechanistic explanation for the p53-depedent changes of chromatin accessibility, with the consequent influence of expression and rearrangement of these genomic sites in pancreatic cancer. Overall, these data suggest a potential functional and biochemical regulatory network connecting p53 and nuclear architecture.

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“…Tetraploidy followed by aneuploidy is a frequent occurrence in Tp53 mutant cancers [50][51][52][53][54][55] . Here we observed that cells with low RNF144B that present increased ploidy, DNA damage and chromosomal aberrations can survive and progress even in the presence of wild-type Tp53.…”

Section: Discussionmentioning

confidence: 99%

The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability

Abad,

Sandoz,

Romero

et al. 2023

Preprint

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The tumor suppressor protein TP53 regulates a vast transcriptional program that serves protective mechanisms against cancer development. However, the complexity of this program makes it difficult to unravel the role of each of its targets in TP53-mediated tumour suppression. Knockdown of RNF144B, a E3-ubiquitin ligase transcriptionally regulated by TP53, enhanced the rate of tumour development and severity of malignant disease in the context of murine c-MYC-driven lymphomagenesis. Here we asked whether RNF144B has an impact on tumor suppression beyond the hematopoietic compartment. Integrative transcriptomics, proteomics, genomics and functional analysis of human and mouse oncogene-expressing cells with TP53 wild-type revealed a role for RNF144B in coordinating cellular proliferation and transformation, DNA repair and genome stability. Moreover, we show that in the context of lung adenocarcinomas, RNF144B deficiency leads to resistance to cytotoxic drugs that induce DNA damage and chromosomal instability, and that patients have a worse disease-survival overall. Supported by clinical data, our study suggests that RNF144B governs genomic stability during transformation suppression, which could explain its inactivation in human cancers.

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

Cited by 19 publications

References 45 publications

Developmental priming of cancer susceptibility

Developmental priming of cancer susceptibility

p53 regulates expression of nuclear envelope components in cancer cells

The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability

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