Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.

Autor: Reynolds JJ; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK., Bicknell LS; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Carroll P; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Higgs MR; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK., Shaheen R; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Murray JE; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Papadopoulos DK; Max-Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany., Leitch A; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Murina O; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Tarnauskaitė Ž; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Wessel SR; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA., Zlatanou A; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK., Vernet A; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK., von Kriegsheim A; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Mottram RM; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK., Logan CV; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Bye H; Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK., Li Y; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany., Brean A; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK., Maddirevula S; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Challis RC; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Skouloudaki K; Max-Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany., Almoisheer A; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Alsaif HS; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Amar A; Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK., Prescott NJ; Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK., Bober MB; Nemours-Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA., Duker A; Nemours-Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA., Faqeih E; Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Seidahmed MZ; Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia., Al Tala S; Armed Forces Hospital, SR. P.D. Genetic Unit. Khamis Mushayt, Saudi Arabia., Alswaid A; Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia., Ahmed S; Department of Genetic Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.; Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia., Al-Aama JY; Department of Genetic Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.; Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia., Altmüller J; Cologne Center for Genomics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany., Al Balwi M; Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia., Brady AF; North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Harrow, UK., Chessa L; Department of Clinical and Molecular Medicine, University La Sapienza, Roma, Italy., Cox H; West Midlands Regional Clinical Genetics Service, Birmingham Women's Hospital, West Midlands, UK., Fischetto R; Pediatric Hospital Giovanni XXIII, Bari, Italy., Heller R; Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany., Henderson BD; Divison of Clinical Genetics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa., Hobson E; Department of Genetics, Yorkshire Regional Genetic service, Chapel Allerton Hospital, Leeds, UK., Nürnberg P; Cologne Center for Genomics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany., Percin EF; Department of Medical Genetics, Gazi University Faculty of Medicine, Besevler Ankara, Turkey., Peron A; Clinical Genetics Unit, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, V. Buzzi Children's Hospital, Universita' degli Studi di Milano, Milan, Italy.; Child Neuropsychiatry Unit-Epilepsy Center, San Paolo University Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy., Spaccini L; Clinical Genetics Unit, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, V. Buzzi Children's Hospital, Universita' degli Studi di Milano, Milan, Italy., Quigley AJ; Dept of Radiology, Royal Hospital for Sick Children, Edinburgh, UK., Thakur S; Department of Genetic and Fetal Medicine, Fortis Lafemme, New Delhi, India., Wise CA; Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA., Yoon G; Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto, Toronto, Canada.; Department of Pediatrics, Division of Neurology, Hospital for Sick Children, University of Toronto, Toronto, Canada., Alnemer M; Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Tomancak P; Max-Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany., Yigit G; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany., Taylor AM; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK., Reijns MA; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Simpson MA; Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK., Cortez D; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA., Alkuraya FS; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Mathew CG; Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK.; Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Jackson AP; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK., Stewart GS; Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2017 Apr; Vol. 49 (4), pp. 537-549. Date of Electronic Publication: 2017 Feb 13.
DOI: 10.1038/ng.3790
Abstrakt: To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.
Databáze: MEDLINE