美国宾夕法尼亚大学Roger A. Greenberg等研究人员合作发现，SPATA5-SPATA5L1 ATP酶复合物指导复制体蛋白稳态来确保基因组完整性。相关论文于2024年3月29日在线发表在《细胞》杂志上。
研究人员确定了复制体因子与由AAA+ ATP酶SPATA5-SPATA5L1和异源二聚体伙伴C1orf109-CINP（55LCC）组成的蛋白复合物的相互作用。综合结构生物学方法揭示了SPATA5-SPATA5L1 N端结构域与C1orf109-CINP相互作用的分子结构，从而在圆柱形ATP酶马达上方形成漏斗状结构。
55LCC复合物缺乏会引起泛素依赖性蛋白毒性、复制应激和严重的染色体不稳定性。55LCC的ATP酶活性在复制叉DNA的作用下特异性增强，并与半胱氨酸蛋白酶依赖性的复制体底物切割结合在一起，以应对复制叉损伤。这些发现确定了55LCC介导的蛋白稳态对复制叉的进展和基因组的稳定至关重要，并为相关人类神经发育疾病中的致病变体提供了理论依据。
据悉，VCP/p97对CMG螺旋酶的泛素依赖性去折叠是终止DNA复制所需的。其他复制体成分并不是以同样的方式处理的，这表明复制蛋白的周转还需要其他机制。
附：英文原文
Title: The SPATA5-SPATA5L1 ATPase complex directs replisome proteostasis to ensure genome integrity
Author: Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, Roger A. Greenberg
Issue&Volume: 2024-03-29
Abstract: Ubiquitin-dependent unfolding of the CMG helicase by VCP/p97 is required to terminateDNA 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-SPATA5L1N-terminal domains interacting with C1orf109-CINP to form a funnel-like structureabove a cylindrically shaped ATPase motor. Deficiency in the 55LCC complex elicitedubiquitin-independent proteotoxicity, replication stress, and severe chromosome instability.55LCC showed ATPase activity that was specifically enhanced by replication fork DNAand was coupled to cysteine protease-dependent cleavage of replisome substrates inresponse to replication fork damage. These findings define 55LCC-mediated proteostasisas critical for replication fork progression and genome stability and provide a rationalefor pathogenic variants seen in associated human neurodevelopmental disorders.
DOI: 10.1016/j.cell.2024.03.002
Source: https://www.cell.com/cell/abstract/S0092-8674(24)00250-2