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 MaddirevulaRachel 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

Research output: Contribution to journalArticle

29 Scopus citations

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 languageEnglish (US)
Pages (from-to)537-549
Number of pages13
JournalNature genetics
Volume49
Issue number4
DOIs
StatePublished - Mar 30 2017

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ASJC Scopus subject areas

  • Genetics

Cite this

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