Gallina Irene, Colding Camilla, Henriksen Peter, Beli Petra, Nakamura Kyosuke, Offman Judith, Mathiasen David P, Silva Sonia, Hoffmann Eva, Groth Anja, Choudhary Chunaram, Lisby Michael
Department of Biology, University of Copenhagen, Room 4.1.07, Copenhagen N DK-2200, Denmark.
The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark.
Nat Commun. 2015 Mar 30;6:6533. doi: 10.1038/ncomms7533.
DNA replication stress is a source of genomic instability. Here we identify changed mutation rate 1 (Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that Cmr1--together with Mrc1/Claspin, Pph3, the chaperonin containing TCP1 (CCT) and 25 other proteins--define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to Cmr1, its human orthologue WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that Cmr1/WDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins.
DNA复制应激是基因组不稳定的一个来源。在这里，我们鉴定出变化的突变率1（Cmr1）是参与酿酒酵母对DNA复制应激反应的一个因子，并表明Cmr1与Mrc1/Claspin、Pph3、含TCP1的伴侣蛋白（CCT）以及其他25种蛋白质一起，定义了一个新的核内质量控制区室（INQ），该区域在基因毒性应激反应中隔离错误折叠、泛素化和类泛素化修饰的蛋白质。定位于INQ的蛋白质的多样性表明，其他生物学过程，如细胞周期进程、染色质和有丝分裂纺锤体组织，也可能通过INQ受到调控。与其人类同源物WDR76相似，Cmr1通过重新定位到核灶并与CCT物理结合来响应蛋白酶体抑制和DNA损伤，这表明其具有进化上保守的生物学功能。我们提出，Cmr1/WDR76通过调节类泛素化修饰和磷酸化蛋白质的周转，在从基因毒性应激中恢复的过程中发挥作用。
