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

Authors

Yongtai Bai, Zhe Zhou, Xueqing Yan, Xin Li, Yuyang Dong, Tingyang Zhou, Ye Xiao, Manfei Si, Qiang Liu, Jingying Peng, Chengqi Yi

Published in

Molecular cell. Oct 13, 2026. Epub Oct 13, 2026.

Abstract

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.

PMID:
42869010
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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