Genetic determinants of micronucleus formation in vivo.

Autor: Adams DJ; Wellcome Sanger Institute, Cambridge, UK. da1@sanger.ac.uk., Barlas B; UK Dementia Research Institute at the University of Cambridge, University of Cambridge, Cambridge, UK.; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., McIntyre RE; Wellcome Sanger Institute, Cambridge, UK., Salguero I; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK., van der Weyden L; Wellcome Sanger Institute, Cambridge, UK., Barros A; Wellcome Sanger Institute, Cambridge, UK.; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK., Vicente JR; UK Dementia Research Institute at the University of Cambridge, University of Cambridge, Cambridge, UK.; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Karimpour N; UK Dementia Research Institute at the University of Cambridge, University of Cambridge, Cambridge, UK.; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Haider A; UK Dementia Research Institute at the University of Cambridge, University of Cambridge, Cambridge, UK.; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Ranzani M; Wellcome Sanger Institute, Cambridge, UK., Turner G; Wellcome Sanger Institute, Cambridge, UK., Thompson NA; Wellcome Sanger Institute, Cambridge, UK., Harle V; Wellcome Sanger Institute, Cambridge, UK., Olvera-León R; Wellcome Sanger Institute, Cambridge, UK., Robles-Espinoza CD; Wellcome Sanger Institute, Cambridge, UK.; Laboratorio Internacional de Investigación Sobre el Genoma Humano, Universidad Nacional Autónoma de México, Santiago de Querétaro, México., Speak AO; Wellcome Sanger Institute, Cambridge, UK., Geisler N; Wellcome Sanger Institute, Cambridge, UK.; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK., Weninger WJ; Division of Anatomy, MIC, Medical University of Vienna, Wien, Austria., Geyer SH; Division of Anatomy, MIC, Medical University of Vienna, Wien, Austria., Hewinson J; Wellcome Sanger Institute, Cambridge, UK., Karp NA; Wellcome Sanger Institute, Cambridge, UK., Fu B; Wellcome Sanger Institute, Cambridge, UK., Yang F; Wellcome Sanger Institute, Cambridge, UK., Kozik Z; Functional Proteomics Group, Chester Beatty Laboratories, The Institute of Cancer Research, London, UK., Choudhary J; Functional Proteomics Group, Chester Beatty Laboratories, The Institute of Cancer Research, London, UK., Yu L; Functional Proteomics Group, Chester Beatty Laboratories, The Institute of Cancer Research, London, UK., van Ruiten MS; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Rowland BD; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Lelliott CJ; Wellcome Sanger Institute, Cambridge, UK., Del Castillo Velasco-Herrera M; Wellcome Sanger Institute, Cambridge, UK., Verstraten R; Wellcome Sanger Institute, Cambridge, UK., Bruckner L; Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, Berlin, Germany.; Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany., Henssen AG; Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, Berlin, Germany.; Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.; Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.; German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany., Rooimans MA; Department of Human Genetics, Section of Oncogenetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands., de Lange J; Department of Human Genetics, Section of Oncogenetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands., Mohun TJ; Division of Developmental Biology, MRC, National Institute for Medical Research, London, UK., Arends MJ; Division of Pathology, Cancer Research UK Scotland Centre, Institute of Genetics & Cancer The University of Edinburgh, Edinburgh, UK., Kentistou KA; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK., Coelho PA; Department of Genetics, University of Cambridge, Cambridge, UK., Zhao Y; UK Dementia Research Institute at the University of Cambridge, University of Cambridge, Cambridge, UK.; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Zecchini H; Metabolic Research Laboratory, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK., Perry JRB; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.; Metabolic Research Laboratory, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK., Jackson SP; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.; Cancer Research UK Cambridge Institute, Cambridge, UK., Balmus G; Wellcome Sanger Institute, Cambridge, UK. gb318@cam.ac.uk.; UK Dementia Research Institute at the University of Cambridge, University of Cambridge, Cambridge, UK. gb318@cam.ac.uk.; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. gb318@cam.ac.uk.; The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK. gb318@cam.ac.uk.; Department of Molecular Neuroscience, Transylvanian Institute of Neuroscience, Cluj-Napoca, Romania. gb318@cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Mar; Vol. 627 (8002), pp. 130-136. Date of Electronic Publication: 2024 Feb 14.
DOI: 10.1038/s41586-023-07009-0
Abstrakt: Genomic instability arising from defective responses to DNA damage 1 or mitotic chromosomal imbalances 2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology 1 .
(© 2024. The Author(s).)
Databáze: MEDLINE
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