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M6A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype.

ABSTRACT: 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.

SUBMITTER: Liu P 

PROVIDER: S-EPMC8035315 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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m<sup>6</sup>A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype.

Liu Pingyu P   Li Fuming F   Lin Jianhuang J   Fukumoto Takeshi T   Nacarelli Timothy T   Hao Xue X   Kossenkov Andrew V AV   Simon M Celeste MC   Zhang Rugang R  

Nature cell biology 20210401 4

Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex that catalyses messenger RNA N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification. Despite the expanding list of m<sup>6</sup>A-dependent functions of the methyltransferase complex, the m<sup>6</sup>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 the senescence-a  ...[more]

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