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MTBP phosphorylation controls DNA replication origin firing

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Item Type:Article
Title:MTBP phosphorylation controls DNA replication origin firing
Creators Name:Ferreira, P. and Höfer, V. and Kronshage, N. and Marko, A. and Reusswig, K.U. and Tetik, B. and Dießel, C. and Köhler, K. and Tschernoster, N. and Altmüller, J. and Schulze, N. and Pfander, B. and Boos, D.
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.
Keywords:Binding Sites, Carrier Proteins, Cell Line, Conserved Sequence, Cyclin-Dependent Kinases, DNA Damage, DNA Replication, DNA-Binding Proteins, Phosphorylation, Post-Translational Protein Processing, Protein Binding, Replication Origin, Animals
Source:Scientific Reports
Publisher:Nature Publishing Group
Page Range:4242
Date:19 February 2021
Official Publication:https://doi.org/10.1038/s41598-021-83287-w
PubMed:View item in PubMed

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