MTBP phosphorylation controls DNA replication origin firing.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
19 02 2021
19 02 2021
Historique:
received:
23
08
2020
accepted:
28
01
2021
entrez:
20
2
2021
pubmed:
21
2
2021
medline:
15
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33608586
doi: 10.1038/s41598-021-83287-w
pii: 10.1038/s41598-021-83287-w
pmc: PMC7895959
doi:
Substances chimiques
Carrier Proteins
0
DNA-Binding Proteins
0
MTBP protein, human
0
Cyclin-Dependent Kinases
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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