Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

John J Reynolds; Louise S Bicknell; Paula Carroll; Martin R Higgs; Ranad Shaheen; Jennie E Murray; Dimitrios K Papadopoulos; Andrea Leitch; Olga Murina; Žygimantė Tarnauskaitė; Sarah R Wessel; Anastasia Zlatanou; Audrey Vernet; Alex von Kriegsheim; Rachel M A Mottram; Clare V Logan; Hannah Bye; Yun Li; Alexander Brean; Sateesh Maddirevula; Rachel C Challis; Kassiani Skouloudaki; Agaadir Almoisheer; Hessa S Alsaif; Ariella Amar; Natalie J Prescott; Michael B Bober; Angela Duker; Eissa Faqeih; Mohammed Zain Seidahmed; Saeed Al Tala; Abdulrahman Alswaid; Saleem Ahmed; Jumana Yousuf Al-Aama; Janine Altmüller; Mohammed Al Balwi; Angela F Brady; Luciana Chessa; Helen Cox; Rita Fischetto; Raoul Heller; Bertram D Henderson; Emma Hobson; Peter Nürnberg; E Ferda Percin; Angela Peron; Luigina Spaccini; Alan J Quigley; Seema Thakur; Carol A Wise; Grace Yoon; Maha Alnemer; Pavel Tomancak; Gökhan Yigit; A Malcolm R Taylor; Martin A M Reijns; Michael A Simpson; David Cortez; Fowzan S Alkuraya; Christopher G Mathew; Andrew P Jackson; Grant S Stewart

doi:10.1038/ng.3790

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Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

Journal article

Peer reviewed

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

John J Reynolds, Louise S Bicknell, Paula Carroll, Martin R Higgs, Ranad Shaheen, Jennie E Murray, Dimitrios K Papadopoulos, Andrea Leitch, Olga Murina, Žygimantė Tarnauskaitė, …

Nature genetics, Vol.49(4), pp.537-549

01/04/2017

DOI: https://doi.org/10.1038/ng.3790

PMCID: PMC5450907

PMID: 28191891

Abstract

Cell Line

DNA Damage - genetics

DNA Replication - genetics

DNA-Binding Proteins - genetics

Dwarfism - genetics

Female

Genomic Instability - genetics

Humans

Male

Microcephaly - genetics

Mutation - genetics

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.

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Title: Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism
Creators - without role: John J Reynolds - University of Birmingham
Louise S Bicknell - University of Edinburgh
Paula Carroll - University of Edinburgh
Martin R Higgs - University of Birmingham
Ranad Shaheen - Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Jennie E Murray - University of Edinburgh
Dimitrios K Papadopoulos - Max Planck Institute of Molecular Cell Biology and Genetics
Andrea Leitch - MRC Institute of Genetics and Molecular Medicine
Olga Murina - MRC Institute of Genetics and Molecular Medicine
Žygimantė Tarnauskaitė - MRC Institute of Genetics and Molecular Medicine
Sarah R Wessel - Vanderbilt University
Anastasia Zlatanou - University of Birmingham
Audrey Vernet - University of Birmingham
Alex von Kriegsheim - MRC Institute of Genetics and Molecular Medicine
Rachel M A Mottram - University of Birmingham
Clare V Logan - MRC Institute of Genetics and Molecular Medicine
Hannah Bye - King's College London
Yun Li - Universitätsmedizin Göttingen
Alexander Brean - University of Birmingham
Sateesh Maddirevula - King Faisal Specialist Hospital & Research Centre
Rachel C Challis - MRC Institute of Genetics and Molecular Medicine
Kassiani Skouloudaki - Max Planck Institute of Molecular Cell Biology and Genetics
Agaadir Almoisheer - King Faisal Specialist Hospital & Research Centre
Hessa S Alsaif - King Faisal Specialist Hospital & Research Centre
Ariella Amar - King's College London
Natalie J Prescott - King's College London
Michael B Bober - Alfred I. duPont Hospital for Children
Angela Duker - Alfred I. duPont Hospital for Children
Eissa Faqeih - King Fahd Medical City
Mohammed Zain Seidahmed - Security Forces Hospital
Saeed Al Tala - Armed Forces Hospital
Abdulrahman Alswaid - King Abdulaziz Medical City
Saleem Ahmed - King Abdulaziz Hospital
Jumana Yousuf Al-Aama - King Abdulaziz University
Janine Altmüller - University of Cologne
Mohammed Al Balwi - King Abdulaziz Medical City
Angela F Brady - London North West Healthcare NHS Trust
Luciana Chessa - Sapienza University of Rome
Helen Cox - Birmingham Women's Hospital
Rita Fischetto - Ospedale Pediatrico Giovanni XXIII
Raoul Heller - University Hospital Cologne
Bertram D Henderson - University of the Free State
Emma Hobson - Chapel Allerton Hospital
Peter Nürnberg - University of Cologne
E Ferda Percin - Gazi University
Angela Peron - University of Milan
Luigina Spaccini - University of Milan
Alan J Quigley - Royal Hospital for Sick Children
Seema Thakur - Department of Genetic and Fetal Medicine, Fortis Lafemme, New Delhi, India
Carol A Wise - Texas Scottish Rite Hospital for Children
Grace Yoon - University of Toronto
Maha Alnemer - King Faisal Specialist Hospital & Research Centre
Pavel Tomancak - Max Planck Institute of Molecular Cell Biology and Genetics
Gökhan Yigit - Universitätsmedizin Göttingen
A Malcolm R Taylor - University of Birmingham
Martin A M Reijns - MRC Institute of Genetics and Molecular Medicine
Michael A Simpson - King's College London
David Cortez - Vanderbilt University
Fowzan S Alkuraya - King Faisal Specialist Hospital & Research Centre
Christopher G Mathew - University of the Witwatersrand
Andrew P Jackson - MRC Institute of Genetics and Molecular Medicine
Grant S Stewart - University of Birmingham
Publication Details: Nature genetics, Vol.49(4), pp.537-549
Grant note: 13030 / Cancer Research UK 281847 / European Research Council T32 CA009582 / NCI NIH HHS 13-1012 / Worldwide Cancer Research R01 GM116616 / NIGMS NIH HHS MR/M009882/1 / Medical Research Council MC_PC_U127580972 / Medical Research Council
Identifiers: 9918776108331
Academic Unit: King Faisal University; King Abdulaziz City for Science & Technology; King Abdulaziz University
Language: English
Resource Type: Journal article