TopBP1 utilises a bipartite GINS binding mode to support genome replication

Matthew Day (), Bilal Tetik, Milena Parlak, Yasser Almeida-Hernández, Markus Räschle, Farnusch Kaschani, Heike Siegert, Anika Marko, Elsa Sanchez-Garcia, Markus Kaiser, Isabel A. Barker, Laurence H. Pearl (), Antony W. Oliver () and Dominik Boos ()
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Matthew Day: Queen Mary University of London
Bilal Tetik: University of Duisburg-Essen
Milena Parlak: University of Duisburg-Essen
Yasser Almeida-Hernández: Technical University Dortmund
Markus Räschle: Technical University Kaiserslautern
Farnusch Kaschani: University of Duisburg-Essen
Heike Siegert: University of Duisburg-Essen
Anika Marko: University of Duisburg-Essen
Elsa Sanchez-Garcia: Technical University Dortmund
Markus Kaiser: University of Duisburg-Essen
Isabel A. Barker: University of Sussex, Falmer
Laurence H. Pearl: University of Sussex, Falmer
Antony W. Oliver: University of Sussex, Falmer
Dominik Boos: University of Duisburg-Essen

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Activation of the replicative Mcm2-7 helicase by loading GINS and Cdc45 is crucial for replication origin firing, and as such for faithful genetic inheritance. Our biochemical and structural studies demonstrate that the helicase activator GINS interacts with TopBP1 through two separate binding surfaces, the first involving a stretch of highly conserved amino acids in the TopBP1-GINI region, the second a surface on TopBP1-BRCT4. The two surfaces bind to opposite ends of the A domain of the GINS subunit Psf1. Mutation analysis reveals that either surface is individually able to support TopBP1-GINS interaction, albeit with reduced affinity. Consistently, either surface is sufficient for replication origin firing in Xenopus egg extracts and becomes essential in the absence of the other. The TopBP1-GINS interaction appears sterically incompatible with simultaneous binding of DNA polymerase epsilon (Polε) to GINS when bound to Mcm2-7-Cdc45, although TopBP1-BRCT4 and the Polε subunit PolE2 show only partial competitivity in binding to Psf1. Our TopBP1-GINS model improves the understanding of the recently characterised metazoan pre-loading complex. It further predicts the coordination of three molecular origin firing processes, DNA polymerase epsilon arrival, TopBP1 ejection and GINS integration into Mcm2-7-Cdc45.

Date: 2024
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DOI: 10.1038/s41467-024-45946-0

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