Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

Item Type:	Article
Title:	Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism
Creators Name:	Reynolds, J.J. and Bicknell, L.S. and Carroll, P. and Higgs, M.R. and Shaheen, R. and Murray, J.E. and Papadopoulos, D.K. and Leitch, A. and Murina, O. and Tarnauskaitė, Ž. and Wessel, S.R. and Zlatanou, A. and Vernet, A. and von Kriegsheim, A. and Mottram, R.M.A. and Logan, C.V. and Bye, H. and Li, Y. and Brean, A. and Maddirevula, S. and Challis, R.C. and Skouloudaki, K. and Almoisheer, A. and Alsaif, H.S. and Amar, A. and Prescott, N.J. and Bober, M.B. and Duker, A. and Faqeih, E. and Seidahmed, M.Z. and Al Tala, S. and Alswaid, A. and Ahmed, S. and Al-Aama, J.Y. and Altmüller, J. and Al Balwi, M. and Brady, A.F. and Chessa, L. and Cox, H. and Fischetto, R. and Heller, R. and Henderson, B.D. and Hobson, E. and Nürnberg, P. and Percin, E.F. and Peron, A. and Spaccini, L. and Quigley, A.J. and Thakur, S. and Wise, C.A. and Yoon, G. and Alnemer, M. and Tomancak, P. and Yigit, G. and Taylor, A.M.R. and Reijns, M.A.M. and Simpson, M.A. and Cortez, D. and Alkuraya, F.S. and Mathew, C.G. and Jackson, A.P. and Stewart, G.S.
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, DNA Replication, DNA-Binding Proteins, Dwarfism, Genomic Instability, Microcephaly, Mutation / Genetics
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	49
Number:	4
Page Range:	537-549
Date:	April 2017
Official Publication:	https://doi.org/10.1038/ng.3790
PubMed:	View item in PubMed

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