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| Item Type: | Article |
|---|---|
| Title: | MTBP phosphorylation controls DNA replication origin firing |
| Creators Name: | Ferreira, P., Höfer, V., Kronshage, N., Marko, A., Reusswig, K.U., Tetik, B., Dießel, C., Köhler, K., Tschernoster, N., Altmüller, J., Schulze, N., 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 |
| ISSN: | 2045-2322 |
| Publisher: | Nature Publishing Group |
| Volume: | 11 |
| Number: | 1 |
| 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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