m(6)A independent genome-wide METTL3 and METTL14 redistribution drives senescence-associated secretory phenotype

Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex (MTC) that catalyzes mRNA N(6)-methyladenosine (m(6)A) modification. Despite the expanding list of m(6)A-dependent function of the MTC, m(6)A independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 transcriptionally drives senescence-associated secretory phenotype (SASP) in a m(6)A-independent manner. METTL14 is redistributed to the enhancers, while 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 m(6)A mRNA modification. METTL3 and METTL14 are required for both the tumor-promoting and immune surveillance functions of senescent cells mediated by SASP in vivo in mouse models. In summary, our results report a m(6)A independent function of the METTL3 and METTL14 complex in transcriptionally promoting SASP during senescence.