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The Replication Kinase Cdc7 Marks Histones to Regulate Biosynthesis Genes

ABSTRACT: We demonstrate that the Cdc7/Dbf4-dependent histone modification, H3 threonine 45 phosphorylation (H3T45p), is specifically enriched at origins of replication, and highly transcribed genes involved in protein synthesis and glycolysis. Furthermore, we show that H3T45p also mediates polymerase recruitment and expression of these genes.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE43737 | GEO | 2022/01/09

REPOSITORIES: GEO

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DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks.

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RNA-seq of human breast epithelial cell line MCF10A treated for 8 days with the CDC7 inhibitors XL413, TAK-931 against DMSO-treated controls

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The structural basis of Cdc7-Dbf4 kinase dependent targeting and phosphorylation of the MCM2-7 double hexamer

Project description:The controlled assembly of replication forks is critical for genome stability. The Dbf4-dependent Cdc7 kinase (DDK) initiates replisome assembly by phosphorylating the MCM2-7 replicative helicase at the N-terminal tails of Mcm2, Mcm4 and Mcm6. At present, it remains poorly understood how DDK docks onto the helicase and how the kinase targets distal Mcm subunits for phosphorylation. By cryo-electron microscopy and biochemical analysis we discovered that an interaction between the HBRCT domain of Dbf4 with Mcm2 serves as an anchoring point, which supports binding of DDK across the MCM2-7 double-hexamer interface and phosphorylation of Mcm4 on the opposite hexamer. Moreover, a rotation of DDK along its anchoring point allows phosphorylation of Mcm2 and Mcm6 on opposite hexamers. In summary, our work provides fundamental insights in the DDK structure, control and the selective activation of the MCM2-7 helicase during DNA replication, which can be exploited for development of novel DDK inhibitors.

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DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks.

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Kinetochores coordinate pericentromeric cohesion and early DNA replication by Cdc7-Dbf4 kinase recruitment

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