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In silico protein interaction screening uncovers DONSON's role in replication initiation.
Lim, Yang; Tamayo-Orrego, Lukas; Schmid, Ernst; Tarnauskaite, Zygimante; Kochenova, Olga V; Gruar, Rhian; Muramatsu, Sachiko; Lynch, Luke; Schlie, Aitana Verdu; Carroll, Paula L; Chistol, Gheorghe; Reijns, Martin A M; Kanemaki, Masato T; Jackson, Andrew P; Walter, Johannes C.
Afiliación
  • Lim Y; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA 02115, USA.
  • Tamayo-Orrego L; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
  • Schmid E; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA 02115, USA.
  • Tarnauskaite Z; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
  • Kochenova OV; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA 02115, USA.
  • Gruar R; Howard Hughes Medical Institute, Boston, MA 02115, USA.
  • Muramatsu S; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA 02115, USA.
  • Lynch L; Department of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Mishima, Shizuoka 411-8540, Japan.
  • Schlie AV; Biochemistry Department, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Carroll PL; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
  • Chistol G; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
  • Reijns MAM; Chemical and Systems Biology Department, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Kanemaki MT; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
  • Jackson AP; Department of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Mishima, Shizuoka 411-8540, Japan.
  • Walter JC; Graduate Institute for Advanced Studies, SOKENDAI, Mishima, Shizuoka 411-8540, Japan.
Science ; 381(6664): eadi3448, 2023 09 22.
Article en En | MEDLINE | ID: mdl-37590370
CDC45-MCM2-7-GINS (CMG) helicase assembly is the central event in eukaryotic replication initiation. In yeast, a multi-subunit "pre-loading complex" (pre-LC) accompanies GINS to chromatin-bound MCM2-7, leading to CMG formation. Here, we report that DONSON, a metazoan protein mutated in microcephalic primordial dwarfism, is required for CMG assembly in vertebrates. Using AlphaFold to screen for protein-protein interactions followed by experimental validation, we show that DONSON scaffolds a vertebrate pre-LC containing GINS, TOPBP1, and DNA pol ε. Our evidence suggests that DONSON docks the pre-LC onto MCM2-7, delivering GINS to its binding site in CMG. A patient-derived DONSON mutation compromises CMG assembly and recapitulates microcephalic dwarfism in mice. These results unify our understanding of eukaryotic replication initiation, implicate defective CMG assembly in microcephalic dwarfism, and illustrate how in silico protein-protein interaction screening accelerates mechanistic discovery.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Nucleares / Proteínas de Ciclo Celular / Proteínas de Unión al ADN / Replicación del ADN / Proteínas de Mantenimiento de Minicromosoma Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Animals / Humans Idioma: En Revista: Science Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Nucleares / Proteínas de Ciclo Celular / Proteínas de Unión al ADN / Replicación del ADN / Proteínas de Mantenimiento de Minicromosoma Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Animals / Humans Idioma: En Revista: Science Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos