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TitleThe SPATA5-SPATA5L1 ATPase complex directs replisome proteostasis to ensure genome integrity.
Journal, issue, pagesCell, Vol. 187, Issue 9, Page 2250-2268.e31, Year 2024
Publish dateApr 25, 2024
AuthorsVidhya 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 /
PubMed AbstractUbiquitin-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 ...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.
External linksCell / PubMed:38554706 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2 - 4.5 Å
Structure data

19177

8rhn

EMDB-19177, PDB-8rhn:
Structure of the 55LCC ATPase complex
Method: EM (single particle) / Resolution: 4.5 Å

PDB-8cih:
Structure of FL CINP
Method: X-RAY DIFFRACTION / Resolution: 2.0 Å

Chemicals

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
KeywordsREPLICATION / alpha-helical structure / protein complex subunit / DNA replication / DNA BINDING PROTEIN / AAA+ ATPases / proteostasis

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