Groupe Microtubules et Cycle Cellulaire, Institut de Génétique Humaine, CNRS UPR 1142, Montpellier, France.
Cell Cycle. 2012 Jun 15;11(12):2380-90. doi: 10.4161/cc.20858.
p53 is a key tumor suppressor that controls DNA damage response and genomic integrity. In response to genotoxic stress, p53 is stabilized and activated, resulting in controlled activation of genes involved in cell cycle arrest, DNA repair and/or apoptosis. ASAP is a centrosome- and spindle-associated protein, the deregulation of which induces severe mitotic defects. We show here that following double-strand break DNA formation, ASAP directly interacts with and stabilizes p53 by enhancing its p300-mediated acetylation and blocking its MDM2-mediated ubiquitination and degradation, leading to an increase of p53 transcriptional activity. Upon DNA damage, ASAP is transiently accumulated before being degraded upon persistent damage. This work links the p53 response with the cytoskeleton and confirms that the DNA-damaging signaling pathway is coordinated by centrosomal proteins. We reveal the existence of a new pathway through which ASAP signals the DNA damage response by regulating the p300-MDM2-p53 loop. These results point out ASAP as a possible target for the design of drugs to sensitize radio-resistant tumors.
p53 是一种关键的肿瘤抑制因子，可控制 DNA 损伤反应和基因组完整性。p53 在响应遗传毒性应激时会稳定并激活，从而控制与细胞周期阻滞、DNA 修复和/或细胞凋亡相关的基因的激活。ASAP 是一种中心体和纺锤体相关蛋白，其失调会导致严重的有丝分裂缺陷。我们在这里表明，在双链 DNA 形成后，ASAP 通过增强其 p300 介导的乙酰化并阻止其 MDM2 介导的泛素化和降解，直接与 p53 相互作用并稳定 p53，从而增加 p53 的转录活性。在 DNA 损伤后，ASAP 会在持续损伤后被降解之前短暂积累。这项工作将 p53 反应与细胞骨架联系起来，并证实了 DNA 损伤信号通路是由中心体蛋白协调的。我们揭示了一种新的途径，即 ASAP 通过调节 p300-MDM2-p53 环来发出 DNA 损伤反应信号。这些结果指出 ASAP 可能是设计药物以增敏放射抗性肿瘤的潜在靶点。
