RESUMEN
Senescent cell clearance is emerging as a promising strategy for treating age-related diseases. Senolytics are small molecules that promote the clearance of senescent cells; however, senolytics are uncommon and their underlying mechanisms remain largely unknown. Here, we investigated whether genomic instability is a potential target for senolytic. We screened small-molecule kinase inhibitors involved in the DNA damage response (DDR) in Zmpste24-/- mouse embryonic fibroblasts, a progeroid model characterized with impaired DDR and DNA repair. 4,5,6,7-tetrabromo-2-azabenzamidazole (TBB), which specifically inhibits casein kinase 2 (CK2), was selected and discovered to preferentially trigger apoptosis in Zmpste24-/- cells. Mechanistically, inhibition of CK2 abolished the phosphorylation of heterochromatin protein 1α (HP1α), which retarded the dynamic HP1α dissociation from repressive histone mark H3K9me3 and its relocalization with γH2AX to DNA damage sites, suggesting that disrupting heterochromatin remodeling in the initiation of DDR accelerates apoptosis in senescent cells. Furthermore, feeding Zmpste24-deficient mice with TBB alleviated progeroid features and extended their lifespan. Our study identified TBB as a new class senolytic compound that can reduce age-related symptoms and prolong lifespan in progeroid mice.
Asunto(s)
Quinasa de la Caseína II , Senescencia Celular , Daño del ADN , Longevidad , Proteínas de la Membrana , Metaloendopeptidasas , Animales , Senescencia Celular/efectos de los fármacos , Quinasa de la Caseína II/metabolismo , Quinasa de la Caseína II/antagonistas & inhibidores , Quinasa de la Caseína II/genética , Ratones , Longevidad/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Daño del ADN/efectos de los fármacos , Metaloendopeptidasas/metabolismo , Metaloendopeptidasas/genética , Metaloendopeptidasas/deficiencia , Apoptosis/efectos de los fármacos , Homólogo de la Proteína Chromobox 5/metabolismo , Histonas/metabolismo , Ratones Noqueados , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Proteínas Cromosómicas no Histona/metabolismo , Humanos , Fosforilación/efectos de los fármacosRESUMEN
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.