Evidence map›Paper›PMID 34963704›Full record

ArticleNature structural & molecular biology2022

Structural mechanism for the selective phosphorylation of DNA-loaded MCM double hexamers by the Dbf4-dependent kinase.

Julia F Greiwe, Thomas C R Miller, Julia Locke, Fabrizio Martino, Steven Howell, Anne Schreiber, Andrea Nans, John F X Diffley, Alessandro Costa

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature structural & molecular biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed
2.4field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

32 citing papers in PubMed, 44 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 3 countries.

Julia F GreiweMacromolecular Machines Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0002-5708-7923
Thomas C R MillerMacromolecular Machines Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0002-9749-1656
Julia LockeMacromolecular Machines Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0002-0641-3389
Fabrizio MartinoMacromolecular Machines Laboratory, The Francis Crick Institute, London, UK.
Steven HowellProteomics Science Technology Platform, The Francis Crick Institute, London, UK.
Anne SchreiberCellular Degradation Systems Laboratory, The Francis Crick Institute, London, UK.
Andrea NansStructural Biology Science Technology Platform, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0002-3791-2447
John F X DiffleyChromosome Replication Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0001-5184-7680
Alessandro CostaMacromolecular Machines Laboratory, The Francis Crick Institute, London, UK. alessandro.costa@crick.ac.uk.ORCID http://orcid.org/0000-0003-1126-2498
The Francis Crick Institute · GBUniversity of Copenhagen · DK

Funding

Cancer Research UKWellcome Trust 106252/Z/14/ZWellcome Trust FC001065Wellcome Trust FC001066Wellcome Trust FC001598
6 · The paper itself

Abstract

Loading of the eukaryotic replicative helicase onto replication origins involves two MCM hexamers forming a double hexamer (DH) around duplex DNA. During S phase, helicase activation requires MCM phosphorylation by Dbf4-dependent kinase (DDK), comprising Cdc7 and Dbf4. DDK selectively phosphorylates loaded DHs, but how such fidelity is achieved is unknown. Here, we determine the cryogenic electron microscopy structure of Saccharomyces cerevisiae DDK in the act of phosphorylating a DH. DDK docks onto one MCM ring and phosphorylates the opposed ring. Truncation of the Dbf4 docking domain abrogates DH phosphorylation, yet Cdc7 kinase activity is unaffected. Late origin firing is blocked in response to DNA damage via Dbf4 phosphorylation by the Rad53 checkpoint kinase. DDK phosphorylation by Rad53 impairs DH phosphorylation by blockage of DDK binding to DHs, and also interferes with the Cdc7 active site. Our results explain the structural basis and regulation of the selective phosphorylation of DNA-loaded MCM DHs, which supports bidirectional replication.

Indexed as

Protein MultimerizationAmino Acid SequenceCell Cycle ProteinsCheckpoint Kinase 2DNA, FungalMinichromosome Maintenance Complex Component 4Molecular Docking SimulationNucleotidesPhosphorylationProtein Serine-Threonine KinasesSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsSubstrate SpecificityCDC7 protein, S cerevisiaeCell Cycle ProteinsCheckpoint Kinase 2Dbf4 protein, S cerevisiaeDNA, FungalMCM4 protein, S cerevisiaeMinichromosome Maintenance Complex Component 4NucleotidesProtein Serine-Threonine KinasesRAD53 protein, S cerevisiaeSaccharomyces cerevisiae Proteins

Identifiers

PMID34963704
PMCPMC8770131
OpenAlexW4200441769

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.