IGF2BP3 promotes mRNA degradation through internal m⁷G modification

Recent studies have suggested that mRNA internal m⁷G and its writer protein METTL1 are closely related to cell metabolism and cancer regulation. Here, we identify that IGF2BP family proteins IGF2BP1-3 can preferentially bind internal mRNA m⁷G. Such interactions, especially IGF2BP3 with m⁷G, could promote the degradation of m⁷G target transcripts in cancer cells. IGF2BP3 is more responsive to changes of m⁷G modification, while IGF2BP1 prefers m⁶A to stabilize the bound transcripts. We also demonstrate that p53 transcript, TP53, is m⁷G-modified at its 3'UTR in cancer cells. In glioblastoma, the methylation level and the half lifetime of the modified transcript could be modulated by tuning IGF2BP3, or by site-specific targeting of m⁷G through a dCas13b-guided system, resulting in modulation of cancer progression and chemosensitivity.