A feedback mechanism of m(6)A via PARP1-mediated ADP ribosylation of METTL3/METTL14.

PARP1-mediated ADP ribosylation of METTL3/14 forms a negative feedback loop regulating m6A methylation in human cells.

• Why it matters: Understanding how signaling pathways influence m6A homeostasis is crucial for developing targeted cancer therapies, as current models focus mainly on the "writer/eraser/reader" system.
• What they did: The study identified that IGF2BPs recruit PARP1 to m6A-modified RNAs, stimulating PARP1 activity, which then ADP ribosylates METTL3/14, impairing its RNA binding and reducing m6A deposition, using human cell lines.
• The result: Combining PARP inhibitors with m6A-targeting strategies showed synergistic anti-tumor effects, suggesting new avenues for cancer treatment based on this regulatory mechanism.