PRKN-Mediated Ubiquitin-Proteasome Degradation of METTL3 Promotes Cellular Senescence.

Abstract

N6-methyladenosine (m6A) methylation, a dynamic and reversible modification of eukaryotic mRNAs, plays critical roles in diverse cellular processes. Although METTL3-mediated m6A deposition has been implicated in cellular senescence, the mechanisms controlling METTL3 stability and activity during senescence remain poorly defined. Here, we demonstrate that both m6A levels and METTL3 protein abundance are significantly reduced in replication-induced and stress-induced senescence models. METTL3 depletion promotes senescence by inducing telomere dysfunction via diminished expression of shelterin components TRF2 and POT1. Mechanistically, we identify PRKN (Parkin) as a senescence-associated E3 ubiquitin ligase that promotes METTL3 proteasomal degradation through K48-linked polyubiquitination at lysine 164. Genetic PRKN inhibition in pre-senescent cells rescues METTL3 expression, restores TRF2/POT1 levels, reduces telomere dysfunction-induced foci (TIFs), and attenuates senescence-associated β-galactosidase (SA-β-gal) activity. Crucially, PRKN overexpression accelerates telomere dysfunction and senescence in wild-type METTL3-expressing cells but not in cells expressing the ubiquitination-resistant K164R METTL3 mutant. Our findings establish METTL3 ubiquitination as a pivotal regulator of telomere integrity and senescence progression, unveiling a therapeutic target for age-related pathologies.