RESUMO
Telomere length control is critical for cellular lifespan and tumor suppression. Telomerase is transiently activated in the inner cell mass of the developing blastocyst to reset telomere reserves. Its silencing upon differentiation leads to gradual telomere shortening in somatic cells. Here, we report that transcriptional regulation through cis-regulatory elements only partially accounts for telomerase activation in pluripotent cells. Instead, developmental control of telomerase is primarily driven by an alternative splicing event, centered around hTERT exon 2. Skipping of exon 2 triggers hTERT mRNA decay in differentiated cells, and conversely, its retention promotes telomerase accumulation in pluripotent cells. We identify SON as a regulator of exon 2 alternative splicing and report a patient carrying a SON mutation and suffering from insufficient telomerase and short telomeres. In summary, our study highlights a critical role for hTERT alternative splicing in the developmental regulation of telomerase and implicates defective splicing in telomere biology disorders.
Assuntos
Processamento Alternativo , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos , Antígenos de Histocompatibilidade Menor/genética , Telomerase/genética , Homeostase do Telômero , Telômero/metabolismo , Blastocisto/metabolismo , Blastocisto/patologia , Diferenciação Celular , Pré-Escolar , Proteínas de Ligação a DNA/deficiência , Feminino , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Embrionárias Humanas/patologia , Humanos , Linhagem , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/patologia , Cultura Primária de Células , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Telomerase/deficiência , Telômero/patologiaRESUMO
Telomeres are distinctive structures that protect the ends of linear chromosomes and ensure genome stability. They are composed of long tracks of repetitive and G-rich DNA that is bound by shelterin, a dedicated six-subunit protein complex. In somatic cells, shelterin protects telomeres from the DNA damage response and regulates telomere length. Telomere repeats are replenished by telomerase, a specialized ribonucleoprotein composed of telomerase reverse transcriptase and an integral RNA component. Telomere protection and telomerase regulation have been primarily studied in somatic cells. However, recent evidence points out striking differences in the context of embryonic stem cells (ESCs). In this review, we discuss insights into telomere protection in ESCs versus somatic cells and summarize findings on telomerase regulation as a function of pluripotency.