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

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

Edinburgh Imaging, University of Edinburgh, Edinburgh, UK.
University Hospitals Birmingham , Birmingham , UK.
King Faisal Specialist Hospital and Research Center
Max Planck Institute for Molecular Cell Biology and Genetics, Dresden
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
King's College London University of London London WC2B 4BG UK
Department of NeuroDegeneration and Restorative Research, University Medical Center Göttingen
Nemours-Alfred I. duPont Hospital for Children
Children's Hospital of Philadelphia
Security Forces Hospital
Armed Forces Hospital
Department of Pediatrics, Olga Hospital, Stuttgart, Germany.
King Abdulaziz University Hospital
University Hopsital of Cologne
Department of Pathology and Laboratory Medicine
North West Thames Regional Genetics Service
Università degli Studi di Roma La Sapienza
Oncology, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK. [email protected].; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. [email protected].; Children's Brain Tumour Research Team, 4th Floor Institute of Child Health, Birmingham Women's and Children's Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH, UK. [email protected].
Pediatric Hospital Giovanni XXIII
Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany
University of the Free State
Chapel Allerton Hospital
Gazi University Faculty of Medicine
V. Buzzi Children's Hospital
Royal Belfast Hospital for Sick Children
Department of Genetic and Fetal Medicine
Sarah M. and Charles E. Seay Center for Musculoskeletal Research
Neurosurgery, University of Toronto, Toronto, CAN.
Institute of Cancer and Genomic Sciences; University of Birmingham; Birmingham UK

Research output: Contribution to journal › Article › peer-review

93 Citations (SciVal)

Abstract

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.

Original language	English
Pages (from-to)	537-549
Number of pages	13
Journal	Nature Genetics
Volume	49
Issue number	4
Early online date	13 Feb 2017
DOIs	https://doi.org/10.1038/ng.3790
Publication status	Published - Apr 2017

Keywords

Cell Line
DNA Damage/genetics
DNA Replication/genetics
DNA-Binding Proteins/genetics
Dwarfism/genetics
Female
Genomic Instability/genetics
Humans
Male
Microcephaly/genetics
Mutation/genetics

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10.1038/ng.3790

https://www.research.ed.ac.uk/en/publications/mutations-in-donson-disrupt-replication-fork-stability-and-cause-

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Reynolds, J. J., Bicknell, L. S., Carroll, P., Higgs, M. R., Shaheen, R., Murray, J. E., Papadopoulos, D. K., Leitch, A., Murina, O., Tarnauskaitė, Ž., Wessel, S. R., Zlatanou, A., Vernet, A., von Kriegsheim, A., Mottram, R. M. A., Logan, C. V., Bye, H., Li, Y., Brean, A., ... Stewart, G. S. (2017). Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nature Genetics, 49(4), 537-549. https://doi.org/10.1038/ng.3790

@article{845a0dfc4cab4c2a87eb5b7b5d762cbb,

title = "Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism",

abstract = "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.",

keywords = "Cell Line, DNA Damage/genetics, DNA Replication/genetics, DNA-Binding Proteins/genetics, Dwarfism/genetics, Female, Genomic Instability/genetics, Humans, Male, Microcephaly/genetics, Mutation/genetics",

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

year = "2017",

month = apr,

doi = "10.1038/ng.3790",

language = "English",

volume = "49",

pages = "537--549",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "4",

}

Reynolds, JJ, Bicknell, LS, Carroll, P, Higgs, MR, Shaheen, R, Murray, JE, Papadopoulos, DK, Leitch, A, Murina, O, Tarnauskaitė, Ž, Wessel, SR, Zlatanou, A, Vernet, A, von Kriegsheim, A, Mottram, RMA, Logan, CV, Bye, H, Li, Y, Brean, A, Maddirevula, S, Challis, RC, Skouloudaki, K, Almoisheer, A, Alsaif, HS, Amar, A, Prescott, NJ, Bober, MB, Duker, A, Faqeih, E, Seidahmed, MZ, Al Tala, S, Alswaid, A, Ahmed, S, Al-Aama, JY, Altmüller, J, Al Balwi, M, Brady, AF, Chessa, L, Cox, H, Fischetto, R, Heller, R, Henderson, BD, Hobson, E, Nürnberg, P, Percin, EF, Peron, A, Spaccini, L, Quigley, AJ, Thakur, S, Wise, CA, Yoon, G, Alnemer, M, Tomancak, P, Yigit, G, Taylor, AMR, Reijns, MAM, Simpson, MA, Cortez, D, Alkuraya, FS, Mathew, CG, Jackson, AP & Stewart, GS 2017, 'Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism', Nature Genetics, vol. 49, no. 4, pp. 537-549. https://doi.org/10.1038/ng.3790

TY - JOUR

T1 - Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

AU - Reynolds, John J

AU - Bicknell, Louise S

AU - Carroll, Paula

AU - Higgs, Martin R

AU - Shaheen, Ranad

AU - Murray, Jennie E

AU - Papadopoulos, Dimitrios K

AU - Leitch, Andrea

AU - Murina, Olga

AU - Tarnauskaitė, Žygimantė

AU - Wessel, Sarah R

AU - Zlatanou, Anastasia

AU - Vernet, Audrey

AU - von Kriegsheim, Alex

AU - Mottram, Rachel M A

AU - Logan, Clare V

AU - Bye, Hannah

AU - Li, Yun

AU - Brean, Alexander

AU - Maddirevula, Sateesh

AU - Challis, Rachel C

AU - Skouloudaki, Kassiani

AU - Almoisheer, Agaadir

AU - Alsaif, Hessa S

AU - Amar, Ariella

AU - Prescott, Natalie J

AU - Bober, Michael B

AU - Duker, Angela

AU - Faqeih, Eissa

AU - Seidahmed, Mohammed Zain

AU - Al Tala, Saeed

AU - Alswaid, Abdulrahman

AU - Ahmed, Saleem

AU - Al-Aama, Jumana Yousuf

AU - Altmüller, Janine

AU - Al Balwi, Mohammed

AU - Brady, Angela F

AU - Chessa, Luciana

AU - Cox, Helen

AU - Fischetto, Rita

AU - Heller, Raoul

AU - Henderson, Bertram D

AU - Hobson, Emma

AU - Nürnberg, Peter

AU - Percin, E Ferda

AU - Peron, Angela

AU - Spaccini, Luigina

AU - Quigley, Alan J

AU - Thakur, Seema

AU - Wise, Carol A

AU - Yoon, Grace

AU - Alnemer, Maha

AU - Tomancak, Pavel

AU - Yigit, Gökhan

AU - Taylor, A Malcolm R

AU - Reijns, Martin A M

AU - Simpson, Michael A

AU - Cortez, David

AU - Alkuraya, Fowzan S

AU - Mathew, Christopher G

AU - Jackson, Andrew P

AU - Stewart, Grant S

PY - 2017/4

Y1 - 2017/4

N2 - 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.

AB - 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.

KW - Cell Line

KW - DNA Damage/genetics

KW - DNA Replication/genetics

KW - DNA-Binding Proteins/genetics

KW - Dwarfism/genetics

KW - Female

KW - Genomic Instability/genetics

KW - Humans

KW - Male

KW - Microcephaly/genetics

KW - Mutation/genetics

UR - https://www.nature.com/articles/ng.3790

U2 - 10.1038/ng.3790

DO - 10.1038/ng.3790

M3 - Article

C2 - 28191891

SN - 1061-4036

VL - 49

SP - 537

EP - 549

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

Abstract

Keywords

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