Lamin A safeguards the m⁶A methylase METTL14 nuclear speckle reservoir to prevent cellular senescence

Abstract

Mutations in LMNA gene are frequently identified in patients suffering from a genetic disorder known as Hutchison-Gilford progeria syndrome (HGPS), providing an ideal model for the understanding of the mechanisms of aging. Lamin A, encoded by LMNA, is an essential component of the subnuclear domain-nuclear speckles; however, the functional significance in aging is unclear. Here, we show that Lamin A interacts with the m⁶ A methyltransferases, METTL3 and METTL14 in nuclear speckles. Lamin A deficiency compromises the nuclear speckle METTL3/14 reservoir and renders these methylases susceptible to proteasome-mediated degradation. Moreover, METTL3/14 levels progressively decline in cells undergoing replicative senescence. Overexpression of METTL14 attenuates both replicative senescence and premature senescence. The data reveal an essential role for Lamin A in safeguarding the nuclear speckle reservoir of the m⁶ A methylase METTL14 to antagonize cellular senescence.