The Mettl3 epitranscriptomic writer amplifies p53 stress responses.

The p53 transcription factor drives anti-proliferative gene expression programs in response to diverse stressors, including DNA damage and oncogenic signaling. Here, we seek to uncover new mechanisms through which p53 regulates gene expression using tandem affinity purification/mass spectrometry to identify p53-interacting proteins. This approach identified METTL3, an m6A RNA-methyltransferase complex (MTC) constituent, as a p53 interactor. We find that METTL3 promotes p53 protein stabilization and target gene expression in response to DNA damage and oncogenic signals, by both catalytic activity-dependent and independent mechanisms. METTL3 also enhances p53 tumor suppressor activity in in vivo mouse cancer models and human cancer cells. Notably, METTL3 only promotes tumor suppression in the context of intact p53. Analysis of human cancer genome data further supports the notion that the MTC reinforces p53 function in human cancer. Together, these studies reveal a fundamental role for METTL3 in amplifying p53 signaling in response to cellular stress.

Puma- and Caspase9-mediated apoptosis is dispensable for p53-driven neural crest-based developmental defects.

Inappropriate activation of the p53 transcription factor is thought to contribute to the developmental phenotypes in a range of genetic syndromes. Whether p53 activation drives these developmental phenotypes by triggering apoptosis, cell cycle arrest, or other p53 cellular responses, however, has remained elusive. As p53 hyperactivation in embryonic neural crest cells (NCCs) drives a number of phenotypes, including abnormal craniofacial and neuronal development, we investigate the basis for p53 action in this context. We show that p53-driven developmental defects are associated with the induction of a robust pro-apoptotic transcriptional signature. Intriguingly, however, deleting Puma or Caspase9, which encode key components of the intrinsic apoptotic pathway, does not rescue craniofacial, neuronal or pigmentation defects triggered by p53 hyperactivation in NCCs. Immunostaining analyses for two key apoptosis markers confirm that deleting Puma or Caspase9 does indeed impair p53-hyperactivation-induced apoptosis in NCCs. Furthermore, we demonstrate that p53 hyperactivation does not trigger a compensatory dampening of cell cycle progression in NCCs upon inactivation of apoptotic pathways. Together, our results indicate that p53-driven craniofacial, neuronal and pigmentation defects can arise in the absence of apoptosis and cell cycle arrest, suggesting that p53 hyperactivation can act via alternative pathways to trigger developmental phenotypes.

Cell of Origin Influences Pancreatic Cancer Subtype.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of approximately 9%. An improved understanding of PDAC initiation and progression is paramount for discovering strategies to better detect and combat this disease. Although transcriptomic analyses have uncovered distinct molecular subtypes of human PDAC, the factors that influence subtype development remain unclear. Here, we interrogate the impact of cell of origin and different Trp53 alleles on tumor evolution, using a panel of tractable genetically engineered mouse models. Oncogenic KRAS expression, coupled with Trp53 deletion or point mutation, drives PDAC from both acinar and ductal cells. Gene-expression analysis reveals further that ductal cell-derived and acinar cell-derived tumor signatures are enriched in basal-like and classical subtypes of human PDAC, respectively. These findings highlight cell of origin as one factor that influences PDAC molecular subtypes and provide insight into the fundamental impact that the very earliest events in carcinogenesis can have on cancer evolution. SIGNIFICANCE: Although human PDAC has been classified into different molecular subtypes, the etiology of these distinct subtypes remains unclear. Using mouse genetics, we reveal that cell of origin is an important determinant of PDAC molecular subtype. Deciphering the biology underlying pancreatic cancer subtypes may reveal meaningful distinctions that could improve clinical intervention.This article is highlighted in the In This Issue feature, p. 521.