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Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

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  • John Reynolds
  • Paula Carroll
  • Martin R Higgs
  • Ranad Shaheen
  • Andrea Leitch
  • Zygimante Tarnauskaite
  • Sarah R Wessel
  • Anastasia Zlatanou
  • Audrey Vernet
  • Rachel M A Mottram
  • Hannah Bye
  • Yun Li
  • Alexander Brean
  • Sateesh Maddirevula
  • Kassiani Skouloudaki
  • Agaadir Almoisheer
  • Hessa S Alsaif
  • Ariella Amar
  • Natalie J Prescott
  • Michael Bober
  • Angela Duker
  • Eissa Faqeih
  • Mohammed Zain Seidahmed
  • Saeed Al Tala
  • Abdulrahman Alswaid
  • Saleem Ahmed
  • Jumana Yousuf Al-Aama
  • Janine Altmuller
  • Mohammed Al Balwi
  • Angela F Brady
  • Luciana Chessa
  • Helen Cox
  • Rita Fischetto
  • Raoul Heller
  • Bertram D Henderson
  • Emma Hobson
  • Peter Nurnberg
  • E Ferda Percin
  • Angela Peron
  • Luigina Spaccini
  • Alan J Quigley
  • Seema Thakur
  • Carol A Wise
  • Grace Yoon
  • Maha Alnemer
  • Gokhan Yigit
  • A. Malcolm R. Taylor
  • Michael A Simpson
  • David Cortez
  • Fowsan S Alkuraya
  • Christopher G Mathew
  • Grant S Stewart

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Original languageEnglish
Pages (from-to)537–549
Number of pages13
JournalNature Genetics
Issue number4
Early online date13 Feb 2017
Publication statusPublished - Apr 2017


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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