Institute of Pharmacology and Toxicology, University Zürich-Vetsuisse Zürich, Switzerland ; Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford Oxford, UK.
Front Genet. 2013 Apr 30;4:60. doi: 10.3389/fgene.2013.00060. eCollection 2013.
Ubiquitin-dependent molecular chaperone p97, also known as valosin-containing protein (VCP) or Cdc48, is an AAA ATPase involved in protein turnover and degradation. p97 converts its own ATPase hydrolysis into remodeling activity on a myriad of ubiquitinated substrates from different cellular locations and pathways. In this way, p97 mediates extraction of targeted protein from cellular compartments or protein complexes. p97-dependent protein extraction from various cellular environments maintains cellular protein homeostasis. In recent years, p97-dependent protein extraction from chromatin has emerged as an essential evolutionarily conserved process for maintaining genome stability. Inactivation of p97 segregase activity leads to accumulation of ubiquitinated substrates on chromatin, consequently leading to protein-induced chromatin stress (PICHROS). PICHROS directly and negatively affects multiple DNA metabolic processes, including replication, damage responses, mitosis, and transcription, leading to genotoxic stress and genome instability. By summarizing and critically evaluating recent data on p97 function in various chromatin-associated protein degradation processes, we propose establishing p97 as a genome caretaker.
泛素依赖性分子伴侣 p97，也称为包含 valosin 蛋白 (VCP) 或 Cdc48，是一种参与蛋白质周转和降解的 AAA ATP 酶。p97 将自身的 ATP 酶水解转化为来自不同细胞位置和途径的多种泛素化底物的重塑活性。通过这种方式，p97 介导靶向蛋白从细胞区室或蛋白质复合物中的提取。p97 依赖的从各种细胞环境中提取蛋白质可维持细胞的蛋白质动态平衡。近年来，p97 依赖的从染色质中提取蛋白质已成为维持基因组稳定性的一种必不可少的进化保守过程。p97 分选型酶活性的失活会导致染色质上积累泛素化的底物，从而导致蛋白诱导的染色质应激（PICHROS）。PICHROS 直接且负地影响多种 DNA 代谢过程，包括复制、损伤反应、有丝分裂和转录，导致遗传毒性应激和基因组不稳定。通过总结和批判性评估 p97 在各种与染色质相关的蛋白质降解过程中的功能的最新数据，我们提出将 p97 确立为基因组守护者。
