Ferreira, Pedro, Hoefer, Verena, Kronshage, Nora, Marko, Anika, Reusswig, Karl-Uwe, Tetik, Bilal, Diessel, Christoph, Koehler, Kerstin, Tschernoster, Nikolai, Altmueller, Janine, Schulze, Nina, Pfander, Boris and Boos, Dominik (2021). MTBP phosphorylation controls DNA replication origin firing. Sci Rep, 11 (1). BERLIN: NATURE RESEARCH. ISSN 2045-2322

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ferreira, PedroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoefer, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kronshage, NoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marko, AnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reusswig, Karl-UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tetik, BilalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diessel, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koehler, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tschernoster, NikolaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulze, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfander, BorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boos, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-587006
DOI: 10.1038/s41598-021-83287-w
Journal or Publication Title: Sci Rep
Volume: 11
Number: 1
Date: 2021
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 2045-2322
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/58700

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