Panasenko, O. | Search bioRxiv

bioRxiv2026

METTL1 gene dosage and catalytic activity define a targetable vulnerability in pediatric cancers

METTL1 is responsible for catalyzing N7-methylguanosine (m7G) methylation of tRNAs. METTL1-dependent oncogenic mechanisms include both its methyltransferase catalytic activity and, in specific instances, non-catalytic interactions that maintain aminoacylated tRNA levels in malignant cells. We show that METTL1 copy number gain and elevated expression are a feature of pediatric tumors that are METTL1 dependent, using Cas13-mediated RNA to reduce the threshold of METTL1 mRNA and protein, which disrupts both catalytic and non-catalytic functions. In cell lines with METTL1 gene amplification, specific degradation of METTL1 mRNA impaired colony formation, triggered cell death, and decreased the translation efficiency of a subset of genes enriched for codons decoded m7G-modified tRNAs. METTL1 inhibition was accompanied by downregulation of c-MYC, n-MYC and MCL-1 protein expression. METTL1 silencing synergizes with drugs targeting anti-apoptotic members of the BCL2 family, notably BCL-xL. Importantly, the catalytic activity of METTL1 was required to rescue cells from the deleterious consequences of METTL1 silencing. We conclude that inhibiting the catalytic activity of METTL1 has potential therapeutic efficacy, particularly in tumors with METTL1 amplification. Synergistic combinations with BH3-mimetic drugs may be a promising therapeutic combination.

cancer biology↗

bioRxiv2023

Hsf1 and the molecular chaperone Hsp90 support a "rewiring stress response" leading to an adaptive cell size increase in chronic stress

Cells are exposed to a wide variety of internal and external stresses. Whereas many studies have focused on cellular responses to acute and severe stresses, little is known about how cellular systems adapt to sublethal chronic stresses. Using mammalian cells in culture, we discovered that they adapt to chronic mild stresses of up to two weeks, notably proteotoxic stresses such as heat, by increasing their size and translation, thereby scaling the amount of total protein. These adaptations render them more resilient to persistent and subsequent stresses. We demonstrate that Hsf1, well known for its role in acute stress responses, is required for the cell size increase, and that the molecular chaperone Hsp90 is essential for coupling the cell size increase to augmented translation. We term this translational reprogramming the "rewiring stress response", and propose that this protective process of chronic stress adaptation contributes to the increase in size as cells get older, and that its failure promotes aging.

cell biology↗