A feedback mechanism of m6A via PARP1-mediated ADP ribosylation of METTL3/METTL14.

The current paradigm of N6-methyladenosine (m6A) homeostasis is implemented by a "writer/eraser/reader" system. Whether or not signaling pathways may regulate m6A homeostasis remains unclear. Here, we identify a negative feedback mechanism between m6A reader IGF2BPs and writer METTL3/METTL14 in human cell lines, which is orchestrated by poly(ADP-ribose) polymerase 1 (PARP1)-catalyzed ADP ribosylation. Specifically, IGF2BPs recruit PARP1 to m6A-modified RNAs and stimulate PARP1 activity; the m6A writer METTL3/14 is then ADP ribosylated, which impairs its RNA-binding capability and reduces m6A deposition. Based on the "read-orchestrate-write" mechanism, we combined PARP inhibitor (PARPi) therapy and m6A-targeting strategies (by inhibiting IGF2BP2 or METTL3) and observed synergistic anti-tumor effects. Taken together, this work expands our understanding of the regulatory paradigm of m6A methylation and provides an opportunity to exploit these findings for cancer therapy.