m⁶A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype

Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex that catalyses messenger RNA N⁶-methyladenosine (m⁶A) modification. Despite the expanding list of m⁶A-dependent functions of the methyltransferase complex, the m⁶A-independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 transcriptionally drives the senescence-associated secretory phenotype (SASP) in an m⁶A-independent manner. METTL14 is redistributed to the enhancers, whereas METTL3 is localized to the pre-existing NF-κB sites within the promoters of SASP genes during senescence. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m⁶A mRNA modification. METTL3 and METTL14 are required for both the tumour-promoting and immune-surveillance functions of senescent cells, which are mediated by SASP in vivo in mouse models. In summary, our results report an m⁶A-independent function of the METTL3 and METTL14 complex in transcriptionally promoting SASP during senescence.