Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

• Published in: Nature genetics Vol. 49; no. 4; pp. 537 - 549
• Main Authors: Reynolds, John J, Bicknell, Louise S, Carroll, Paula, Higgs, Martin R, Shaheen, Ranad, Murray, Jennie E, Papadopoulos, Dimitrios K, Leitch, Andrea, Murina, Olga, Tarnauskaitė, Žygimantė, Wessel, Sarah R, Zlatanou, Anastasia, Vernet, Audrey, von Kriegsheim, Alex, Mottram, Rachel M A, Logan, Clare V, Bye, Hannah, Li, Yun, Brean, Alexander, Maddirevula, Sateesh, Challis, Rachel C, Skouloudaki, Kassiani, Almoisheer, Agaadir, Alsaif, Hessa S, Amar, Ariella, Prescott, Natalie J, Bober, Michael B, Duker, Angela, Faqeih, Eissa, Seidahmed, Mohammed Zain, Al Tala, Saeed, Alswaid, Abdulrahman, Ahmed, Saleem, Al-Aama, Jumana Yousuf, Altmüller, Janine, Al Balwi, Mohammed, Brady, Angela F, Chessa, Luciana, Cox, Helen, Fischetto, Rita, Heller, Raoul, Henderson, Bertram D, Hobson, Emma, Nürnberg, Peter, Percin, E Ferda, Peron, Angela, Spaccini, Luigina, Quigley, Alan J, Thakur, Seema, Wise, Carol A, Yoon, Grace, Alnemer, Maha, Tomancak, Pavel, Yigit, Gökhan, Taylor, A Malcolm R, Reijns, Martin A M, Simpson, Michael A, Cortez, David, Alkuraya, Fowzan S, Mathew, Christopher G, Jackson, Andrew P, Stewart, Grant S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-04-2017; Nature Publishing Group
• Subjects: 13/106; 13/89; 14/19; 14/35; 14/63; 631/208/366; 631/80; 692/699/375/366; 82/58; Agriculture; Animal Genetics and Genomics; Biomedicine; Cancer Research; Cell Line; Cellular proteins; Councils; Deoxyribonucleic acid; Development and progression; DNA; DNA Damage - genetics; DNA Replication - genetics; DNA-Binding Proteins - genetics; Dwarfism; Dwarfism - genetics; Experiments; Female; Funding; Gene Function; Gene mutation; Genes; Genetic aspects; Genomes; Genomic Instability - genetics; Health aspects; Human Genetics; Humans; Male; Mass spectrometry; Medical research; Microcephaly; Microcephaly - genetics; Mutation; Mutation - genetics; Scientific imaging; Studies
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3790

Grant Stewart, Andrew Jackson, Christopher Mathew, Fowzan Alkuraya and colleagues identify a novel replication fork protein, DONSON, which is important for maintaining genome stability. Mutations in
DONSON
cause microcephalic dwarfism and lead to stalled replication forks and DNA damage.
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.