RESUMEN
Microsatellite instability-high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion and cell proliferation and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses the expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.
Asunto(s)
Proteínas de Ciclo Celular , Proteínas Ribosómicas , Humanos , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Neoplasias/genética , Neoplasias/patología , Neoplasias/metabolismo , Línea Celular Tumoral , Empalme Alternativo/genética , Proliferación Celular/genética , Animales , Exones/genética , Ratones , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Regulación Neoplásica de la Expresión Génica , Piperazinas/farmacología , Imidazoles/farmacologíaRESUMEN
Although numerous studies have demonstrated that poor sleep increases the development of AD, direct evidence elucidating the benefits of good sleep on the AD pathogenesis is lacking. Familial Natural Short Sleepers (FNSS) are genetically wired to have lifelong reduction in nightly sleep duration without evident consequence on cognitive demise, implying that they may have better sleep quality. Here we investigated two FNSS mutations, DEC2-P384R and Npsr1-Y206H, on the development of tau and amyloid pathology in AD-like mouse models. We found that the development of tau pathology is attenuated in the hippocampus of tau mice carrying FNSS mutations. We also found that DEC2-P384R;5XFAD and female Npsr1-Y206H;5XFAD mice exhibit significantly less amyloid plaques than control mice at 6 months of age. Together, these results reveal that these two FNSS alleles are strong genetic modifiers of AD pathology and may confer resilience to the progression of tau pathology and amyloid plaque formation in neurodegeneration.
