Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression.
Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression.
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DOI：
10.1038/ncomms10612
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发表时间：
2016-02-04
影响因子：
16.6
通讯作者：
Hoppe T
中科院分区：
文献类型：
--
作者：
Franz A;Pirson PA;Pilger D;Halder S;Achuthankutty D;Kashkar H;Ramadan K;Hoppe T
DNA复制因子的协调活动是一个高度动态的过程，涉及泛素依赖性调节。在这种情况下，泛素介导的ATP酶CDC-48/p97最近成为确保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的CDC-48/p97底物的时空控制仍然不清楚。在这里，我们报告说，DNA复制叉的进展是由UBXN-3/FAF 1协调。UBXN-3/FAF 1与许可因子CDT-1和其他遍在蛋白结合，从而促进CDC-48/p97依赖性的周转和DNA复制因子复合物的分解。因此，UBXN-3/FAF 1的失活稳定了染色质上的CDT-1和CDC-45/GINS，导致复制叉动力学的严重缺陷，伴随着明显的复制应激，最终导致基因组不稳定。我们的工作确定了CDC-48/p97的一个关键底物选择模块，该模块是秀丽隐杆线虫和人类中染色质相关蛋白降解所需的，与肿瘤发生和衰老有关。 Cdc 48/p97是泛素-蛋白酶体系统的一个重要组成部分，作为一种泛素导向的分离酶，调节多种细胞功能。在这里，作者确定UBXN-3/FAF 1是染色质相关蛋白降解的关键调节因子，它将Cdc 48/p97招募到DNA复制叉。
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. Cdc48/p97 is a key component of the ubiquitin-proteasome system, acting as a ubiquitin-directed segregase to regulate multiple cellular functions. Here the authors identify UBXN-3/FAF1 as a crucial regulator of chromatin-associated protein degradation that recruits Cdc48/p97 to DNA replication forks.