Krishnamoorthy, V., Foglizzo, M. orcid.org/0000-0001-9132-4737, Dilley, R.L. et al. (9 more authors) (2024) The SPATA5-SPATA5L1 ATPase complex directs replisome proteostasis to ensure genome integrity. Cell, 187 (9). pp. 2250-2268. ISSN 0092-8674
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 Elsevier Inc. This is an author produced version of an article published in Cell. Uploaded in accordance with the publisher's self-archiving policy. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/. |
Keywords: | 55LCC; AAA+ ATPase; C1orf109; CINP; SPATA5; SPATA5L1; genome instability; replication stress response; replisome regulation/proteostasis; unfoldase |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Funding Information: | Funder Grant number MRC (Medical Research Council) MR/T029471/1 Wellcome Trust 222531/Z/21/Z Wellcome Trust 220628/Z/20/Z Wellcome Trust 223810/Z/21/Z Wellcome Trust 208385/Z/17/Z BBSRC (Biotechnology & Biological Sciences Research Council) BB/L015056/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 03 Apr 2024 08:49 |
Last Modified: | 29 Mar 2025 01:13 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.cell.2024.03.002 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:211111 |