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Journal Article

MTBP phosphorylation controls DNA replication origin firing

MPS-Authors
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Reußwig,  Karl-Uwe
Pfander, Boris / DNA Replication and Genome Integrity, Max Planck Institute of Biochemistry, Max Planck Society;

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Pfander,  Boris
Pfander, Boris / DNA Replication and Genome Integrity, Max Planck Institute of Biochemistry, Max Planck Society;

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s41598-021-83287-w.pdf
(Publisher version), 3MB

Supplementary Material (public)

41598_2021_83287_MOESM1_ESM.pdf
(Supplementary material), 25MB

Citation

Ferreira, P., Hoefer, V., Kronshage, N., Marko, A., Reußwig, K.-U., Tetik, B., et al. (2021). MTBP phosphorylation controls DNA replication origin firing. Scientific Reports, 11(1): 4242. doi:10.1038/s41598-021-83287-w.


Cite as: https://hdl.handle.net/21.11116/0000-0008-AB20-3
Abstract
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.