MTBP phosphorylation controls DNA replication origin firing

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, MT...

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Autores principales:	Pedro Ferreira, Verena Höfer, Nora Kronshage, Anika Marko, Karl-Uwe Reusswig, Bilal Tetik, Christoph Dießel, Kerstin Köhler, Nikolai Tschernoster, Janine Altmüller, Nina Schulze, Boris Pfander, Dominik Boos
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/92ce71894c5a4deda55584773b6d15ac
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spelling	oai:doaj.org-article:92ce71894c5a4deda55584773b6d15ac2021-12-02T10:54:23ZMTBP phosphorylation controls DNA replication origin firing10.1038/s41598-021-83287-w2045-2322https://doaj.org/article/92ce71894c5a4deda55584773b6d15ac2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83287-whttps://doaj.org/toc/2045-2322Abstract 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.Pedro FerreiraVerena HöferNora KronshageAnika MarkoKarl-Uwe ReusswigBilal TetikChristoph DießelKerstin KöhlerNikolai TschernosterJanine AltmüllerNina SchulzeBoris PfanderDominik BoosNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pedro Ferreira Verena Höfer Nora Kronshage Anika Marko Karl-Uwe Reusswig Bilal Tetik Christoph Dießel Kerstin Köhler Nikolai Tschernoster Janine Altmüller Nina Schulze Boris Pfander Dominik Boos MTBP phosphorylation controls DNA replication origin firing
description	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.
format	article
author	Pedro Ferreira Verena Höfer Nora Kronshage Anika Marko Karl-Uwe Reusswig Bilal Tetik Christoph Dießel Kerstin Köhler Nikolai Tschernoster Janine Altmüller Nina Schulze Boris Pfander Dominik Boos
author_facet	Pedro Ferreira Verena Höfer Nora Kronshage Anika Marko Karl-Uwe Reusswig Bilal Tetik Christoph Dießel Kerstin Köhler Nikolai Tschernoster Janine Altmüller Nina Schulze Boris Pfander Dominik Boos
author_sort	Pedro Ferreira
title	MTBP phosphorylation controls DNA replication origin firing
title_short	MTBP phosphorylation controls DNA replication origin firing
title_full	MTBP phosphorylation controls DNA replication origin firing
title_fullStr	MTBP phosphorylation controls DNA replication origin firing
title_full_unstemmed	MTBP phosphorylation controls DNA replication origin firing
title_sort	mtbp phosphorylation controls dna replication origin firing
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/92ce71894c5a4deda55584773b6d15ac
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MTBP phosphorylation controls DNA replication origin firing

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