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 m⁶A 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 m⁶A methylase METTL14 to antagonize cellular senescence.

中文翻译：

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Lamin A 保护 m6 A 甲基化酶 METTL14 核斑点库以防止细胞衰老。

LMNA基因突变经常在患有 Hutchison-Gilford 早衰综合征 (HGPS) 的遗传疾病的患者中发现，这为了解衰老机制提供了理想的模型。由LMNA编码的 Lamin A是亚核域——核斑点的重要组成部分；然而，衰老的功能意义尚不清楚。在这里，我们展示了 Lamin A 与核斑点中的 m ⁶ A 甲基转移酶 METTL3 和 METTL14 相互作用。Lamin A 缺乏会损害核斑点 METTL3/14 库，并使这些甲基化酶容易受到蛋白酶体介导的降解。此外，在经历复制性衰老的细胞中，METTL3/14 水平逐渐下降。METTL14 的过度表达减弱复制性衰老和过早衰老。数据揭示了 Lamin A 在保护 m ⁶ A 甲基化酶 METTL14的核斑点库以对抗细胞衰老方面的重要作用。