Pola-Véliz Víctor, Carrero David, Sagredo Eduardo A, Inostroza Víctor, Cappelli Claudio, Rivas Solange, Bitrán Mirit, Zambrano Evelyn, Gonzalez Evelin, Morales Fernanda, Manterola Marcia, Montecino Martín, Armisén Ricardo, Marcelain Katherine
Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Institute of Biomedical Sciences, Faculty of Medicine, Universidad Andrés Bello; Millennium Nucleus of Neuroepigenetics and Plasticity; Center for Biomedical Research, Faculty of Medicine, Universidad Andrés Bello, Santiago, Chile; FONDAP Center for Genome Regulation, Faculty of Biological Sciences, Universidad Andrés Bello, Santiago, Chile.
Departamento de Oncología Básico Clínico, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Neoplasia. 2025 Jul 2;67:101204. doi: 10.1016/j.neo.2025.101204.
Accurate chromosome segregation and ribosomal gene expression silencing are essential for maintaining genome integrity, and disruptions in these processes are key for oncogenesis and cancer progression. Here, we demonstrate a novel role for the transcriptional co-repressor SKI in regulating rDNA and pericentromeric heterochromatin (PCH) silencing in human cells. We found that SKI localizes to the rDNA promoter on acrocentric chromosomes and is crucial for maintaining H3K9 trimethylation (H3K9me3) and repressing 45S rRNA gene expression. SKI is also associated with BSR and HSATII satellites within PCH, where is necessary for H3K9 methylation and recruitment of SUV39H1 and HP1α, key players for heterochromatin silencing and centromere function. Consequently, SKI deficiency disrupted centromere integrity and resulted in aberrant chromosome segregation, micronuclei formation, and chromosome instability. The identification of SKI as a key participant in the epigenetic-mediated silencing of pericentromeric and ribosomal DNA provides a fundamental insight, paving the way for new research into the intricate relationship between transcriptional regulation and genome instability during cancer progression, and opening novel opportunities for therapeutic intervention.
准确的染色体分离和核糖体基因表达沉默对于维持基因组完整性至关重要，而这些过程的破坏是肿瘤发生和癌症进展的关键。在此，我们证明了转录共抑制因子SKI在调节人类细胞中核糖体DNA（rDNA）和着丝粒周围异染色质（PCH）沉默方面的新作用。我们发现SKI定位于近端着丝粒染色体上的rDNA启动子，对于维持H3K9三甲基化（H3K9me3）和抑制45S rRNA基因表达至关重要。SKI还与PCH内的BSR和HSATII卫星相关，在那里它对于H3K9甲基化以及异染色质沉默和着丝粒功能的关键参与者SUV39H1和HP1α的募集是必需的。因此，SKI缺陷破坏了着丝粒完整性，导致异常的染色体分离、微核形成和染色体不稳定。将SKI鉴定为着丝粒周围和核糖体DNA表观遗传介导沉默的关键参与者提供了一个基本见解，为癌症进展过程中转录调控与基因组不稳定之间复杂关系的新研究铺平了道路，并为治疗干预开辟了新机会。
