MTBP phosphorylation controls DNA replication origin firing

LSF
58011
Affiliation
Vertebrate DNA Replication Lab, Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany
Ferreira, Pedro;
GND
1088566871
LSF
58010
Affiliation
Vertebrate DNA Replication Lab, Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany
Höfer, Verena;
Affiliation
Vertebrate DNA Replication Lab, Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany
Kronshage, Nora;
LSF
56992
Affiliation
Vertebrate DNA Replication Lab, Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany
Marko, Anika;
ORCID
0000-0003-2544-4145
Affiliation
Max Planck Institute of Biochemistry, DNA Replication and Genome Integrity, Martinsried, Germany
Reusswig, Karl-Uwe;
GND
1318164664
LSF
58941
Affiliation
Vertebrate DNA Replication Lab, Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany
Tetik, Bilal;
Affiliation
Vertebrate DNA Replication Lab, Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany
Dießel, Christoph;
LSF
58009
Affiliation
Vertebrate DNA Replication Lab, Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany
Köhler, Kerstin;
ORCID
0000-0002-6058-9342
Affiliation
Institute of Human Genetics, University Clinics Cologne, Cologne, Germany
Tschernoster, Nikolai;
GND
120823977
ORCID
0000-0003-4372-1521
Affiliation
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
Altmüller, Janine;
GND
1052685668
LSF
50324
Affiliation
Imaging Center Campus Essen, Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany
Schulze, Nina;
Affiliation
Max Planck Institute of Biochemistry, DNA Replication and Genome Integrity, Martinsried, Germany
Pfander, Boris;
ORCID
0000-0003-0018-4375
LSF
56347
Affiliation
Vertebrate DNA Replication Lab, Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany
Boos, Dominik
Faithful genome duplication requires regulation of origin firing to determine loci, timing and efficiency of replisome generation. Established kinase targets for eukaryotic origin firing regulation are the Mcm2-7 helicase, Sld3/Treslin/TICRR and Sld2/RecQL4. We report that metazoan Sld7, MTBP (Mdm2 binding protein), is targeted by at least three kinase pathways. MTBP was phosphorylated at CDK consensus sites by cell cycle cyclin-dependent kinases (CDK) and Cdk8/19-cyclin C. Phospho-mimetic MTBP CDK site mutants, but not non-phosphorylatable mutants, promoted origin firing in human cells. MTBP was also phosphorylated at DNA damage checkpoint kinase consensus sites. Phospho-mimetic mutations at these sites inhibited MTBP’s origin firing capability. Whilst expressing a non-phospho MTBP mutant was insufficient to relieve the suppression of origin firing upon DNA damage, the mutant induced a genome-wide increase of origin firing in unperturbed cells. Our work establishes MTBP as a regulation platform of metazoan origin firing.

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Date Issued:
19.02.2021
URN:
urn:nbn:de:hbz:465-20240823-150256-2
DOI:
10.1038/s41598-021-83287-w
Language:
English
Type of Resource:
Text
Keywords:
Cell biology; Chromosomes; DNA replication; Eukaryote; Fragile sites; Genetics; Origin firing; Phosphorylation; Post-translational modifications
Collection:
E-Publications
Subject categories of the Deutsche Nationalbibliografie:
610 Medical sciences Medicine
Subject categories of the Deutsche Nationalbibliografie:
570 Life science
Hosting institution:
Faculty of Biology, Molekulare Genetik
Hosting institution:
Scientific institutes, Center of Medical Biotechnology (ZMB)
funding:

The publication of this article was supported by the Publication Fund of the University of Duisburg-Essen.

Open Access funding enabled and organized by Projekt DEAL.

This article was funded by Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen (NRW Rueckkehrerfoerderprogramm), José Carreras Leukämie-Stiftung (DJCLS R15/23) and Deutsche Forschungsgemeinschaft (GRK1739).

Info on primary publication:

Ferreira, P., Höfer, V., Kronshage, N. et al. MTBP phosphorylation controls DNA replication origin firing. Sci Rep 11, 4242 (2021). https://doi.org/10.1038/s41598-021-83287-w

Published19 February 2021

version identification:
Version of Record / Verlagsversion

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