Division of Oncology and Molecular Biology, Kanazawa University, Kanazawa, Ishikawa, Japan.
Mol Cell Biol. 2013 Aug;33(16):3113-24. doi: 10.1128/MCB.01597-12. Epub 2013 Jun 10.
The retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many chromatin modifiers. However, the biological and clinical significance of this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in an Rb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction of Rb and ATM regulates DNMT1 protein stability and hence controls the DNA methylation status in the promoters of at least the Ink4a, Shc2, FoxO6, and Noggin genes. Furthermore, we demonstrate that inactivation of pRB promotes Tip60 (acetyltransferase)-dependent ATM activation; allows activated ATM to physically bind to DNMT1, forming a complex with Tip60 and UHRF1 (E3 ligase); and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of the pRB pathway in coordination with aberration in the DNA damage response deregulates DNMT1 stability, leading to an abnormal DNA methylation pattern and malignant progression.
视网膜母细胞瘤肿瘤抑制基因 (RB) 产物因其能够与许多染色质修饰物物理结合，而被认为参与了表观遗传控制基因表达。然而，其活性的生物学和临床意义尚未得到很好的阐明。为了解决这个问题，我们在 Rb 缺陷型小鼠甲状腺 C 细胞肿瘤模型中进行了遗传和表观遗传分析。在这里，我们报告 Rb 和 ATM 的遗传相互作用调节 DNMT1 蛋白稳定性，从而控制 Ink4a、Shc2、FoxO6 和 Noggin 基因启动子的 DNA 甲基化状态。此外，我们证明 pRB 的失活促进了 Tip60（乙酰转移酶）依赖性 ATM 的激活；允许激活的 ATM 与 DNMT1 物理结合，形成与 Tip60 和 UHRF1（E3 连接酶）的复合物；并随后加速由 Tip60 依赖性乙酰化驱动的 DNMT1 泛素化。我们的结果表明，pRB 通路的失活与 DNA 损伤反应的异常协同作用，导致 DNMT1 稳定性失调，导致异常的 DNA 甲基化模式和恶性进展。
