Franz André, Pirson Paul A, Pilger Domenic, Halder Swagata, Achuthankutty Divya, Kashkar Hamid, Ramadan Kristijan, Hoppe Thorsten
Institute for Genetics and CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
Department of Oncology, University of Oxford, Cancer Research UK/Medical Research Council Oxford, Institute for Radiation Oncology, Old Road Campus Research Building, OX3 7DQ Oxford, UK.
Nat Commun. 2016 Feb 4;7:10612. doi: 10.1038/ncomms10612.
The coordinated activity of DNA replication factors is a highly dynamic process that involves ubiquitin-dependent regulation. In this context, the ubiquitin-directed ATPase CDC-48/p97 recently emerged as a key regulator of chromatin-associated degradation in several of the DNA metabolic pathways that assure genome integrity. However, the spatiotemporal control of distinct CDC-48/p97 substrates in the chromatin environment remained unclear. Here, we report that progression of the DNA replication fork is coordinated by UBXN-3/FAF1. UBXN-3/FAF1 binds to the licensing factor CDT-1 and additional ubiquitylated proteins, thus promoting CDC-48/p97-dependent turnover and disassembly of DNA replication factor complexes. Consequently, inactivation of UBXN-3/FAF1 stabilizes CDT-1 and CDC-45/GINS on chromatin, causing severe defects in replication fork dynamics accompanied by pronounced replication stress and eventually resulting in genome instability. Our work identifies a critical substrate selection module of CDC-48/p97 required for chromatin-associated protein degradation in both Caenorhabditis elegans and humans, which is relevant to oncogenesis and aging.
DNA复制因子的协同活动是一个高度动态的过程，涉及泛素依赖性调控。在这种情况下，泛素导向的ATP酶CDC-48/p97最近成为保证基因组完整性的几种DNA代谢途径中染色质相关降解的关键调节因子。然而，在染色质环境中不同CDC-48/p97底物的时空控制仍不清楚。在这里，我们报告DNA复制叉的进展由UBXN-3/FAF1协调。UBXN-3/FAF1与许可因子CDT-1和其他泛素化蛋白结合，从而促进CDC-48/p97依赖性的DNA复制因子复合物的周转和拆卸。因此，UBXN-3/FAF1的失活使CDT-实和CDC-45/GINS在染色质上稳定，导致复制叉动力学出现严重缺陷，并伴有明显的复制应激，最终导致基因组不稳定。我们的工作确定了秀丽隐杆线虫和人类中染色质相关蛋白降解所需的CDC-48/p97的关键底物选择模块，这与肿瘤发生和衰老相关。
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