生物
回复
蛋白质稳态
解旋酶
DNA复制
细胞生物学
微小染色体维持
AAA蛋白
原点识别复合体
真核细胞DNA复制
ATP酶
复制因子C
遗传学
复制前复合体
泛素
DNA
基因
生物化学
酶
核糖核酸
作者
Vidhya Krishnamoorthy,Martina Foglizzo,Robert L. Dilley,Angela Ruohao Wu,Asoke G. Datta,Parul Dutta,Louise J. Campbell,Oksana Degtjarik,Laura J. Musgrove,Antonio N. Calabrese,Elton Zeqiraj,Roger A. Greenberg
出处
期刊:Cell
[Elsevier]
日期:2024-03-01
标识
DOI:10.1016/j.cell.2024.03.002
摘要
Ubiquitin-dependent unfolding of the CMG helicase by VCP/p97 is required to terminate DNA replication. Other replisome components are not processed in the same fashion, suggesting that additional mechanisms underlie replication protein turnover. Here, we identify replisome factor interactions with a protein complex composed of AAA+ ATPases SPATA5-SPATA5L1 together with heterodimeric partners C1orf109-CINP (55LCC). An integrative structural biology approach revealed a molecular architecture of SPATA5-SPATA5L1 N-terminal domains interacting with C1orf109-CINP to form a funnel-like structure above a cylindrically shaped ATPase motor. Deficiency in the 55LCC complex elicited ubiquitin-independent proteotoxicity, replication stress, and severe chromosome instability. 55LCC showed ATPase activity that was specifically enhanced by replication fork DNA and was coupled to cysteine protease-dependent cleavage of replisome substrates in response to replication fork damage. These findings define 55LCC-mediated proteostasis as critical for replication fork progression and genome stability and provide a rationale for pathogenic variants seen in associated human neurodevelopmental disorders.
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