Department of Differentiation and Cancer, Center for Genomic Regulation (CRG), and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Oncogene. 2013 Apr 25;32(17):2161-8. doi: 10.1038/onc.2012.241. Epub 2012 Jun 25.
The reactivation of the INK4-ARF locus, which is epigenetically repressed by Polycomb proteins in healthy cells, is a hallmark of senescence. One mechanism of reactivating Polycomb-silenced genes is mediated by the epigenetic factor ZRF1, which associates with ubiquitinated histone H2A. We show that cells undergoing senescence following oncogenic Ras expression have increased ZRF1 levels, and that this binds to the p15INK4b, ARF and p16INK4a promoters. Furthermore, ZRF1 depletion in oncogenic Ras-expressing cells restores proliferation by preventing Arf and p16Ink4a expression, consequently bypassing senescence. Thus, ZRF1 regulates the INK4-ARF locus during cellular proliferation and senescence, and alterations in ZRF1 may contribute to tumorigenesis.
INK4-ARF 基因座的重新激活是衰老的一个标志，在健康细胞中，该基因座被 Polycomb 蛋白通过表观遗传抑制。重新激活 Polycomb 沉默基因的一种机制是由表观遗传因子 ZRF1 介导的，它与泛素化的组蛋白 H2A 结合。我们发现，表达致癌性 Ras 后发生衰老的细胞中 ZRF1 水平增加，并且该蛋白与 p15INK4b、ARF 和 p16INK4a 启动子结合。此外，在表达致癌性 Ras 的细胞中耗尽 ZRF1 可通过防止 Arf 和 p16Ink4a 的表达来恢复增殖，从而绕过衰老。因此，ZRF1 在细胞增殖和衰老过程中调节 INK4-ARF 基因座，ZRF1 的改变可能导致肿瘤发生。
