Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism
| Autor: | Hessa S. Alsaif, Natalie J. Prescott, Dimitrios K. Papadopoulos, Martin R. Higgs, Sarah R. Wessel, Alex von Kriegsheim, David Cortez, Saleem Ahmed, Clare V. Logan, Andrea Leitch, Paula Carroll, B D Henderson, Olga Murina, Jumana Y. Al-Aama, Rachel M A Mottram, Janine Altmüller, Maha Alnemer, Peter Nürnberg, Audrey Vernet, Anastasia Zlatanou, Eissa Faqeih, John J. Reynolds, Louise S. Bicknell, Jennie E. Murray, Angela L. Duker, Ariella Amar, Sateesh Maddirevula, Alexander Brean, Luigina Spaccini, Mohammed Zain Seidahmed, Helen Cox, Mohammed Al Balwi, Carol Wise, Angela Peron, Kassiani Skouloudaki, Rachel C. Challis, Emma Hobson, Fowzan S. Alkuraya, Michael B. Bober, Abdulrahman Alswaid, Grant S. Stewart, Michael A. Simpson, E. Ferda Percin, Angela F. Brady, Hannah Bye, Raoul Heller, Gökhan Yigit, Žygimantė Tarnauskaitė, Grace Yoon, Christopher G. Mathew, Pavel Tomancak, Martin A M Reijns, Agaadir Almoisheer, Ranad Shaheen, Saeed Al Tala, Andrew P. Jackson, Alan J. Quigley, Yun Li, A. Malcolm R. Taylor, Rita Fischetto, Luciana Chessa, Seema Thakur |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genome instability DNA Replication Male DNA damage Dwarfism Biology DNA-binding protein Article Genomic Instability Cell Line 03 medical and health sciences Chromosome instability Gene duplication Genetics medicine Humans DNA replication medicine.disease DNA-Binding Proteins 030104 developmental biology Mutation Microcephaly Replisome Female DNA Damage |
| Zdroj: | Reynolds, J, Bicknell, L S, Carroll, P, Higgs, M R, Shaheen, R, Murray, J E, Papadopoulos, D K, Leitch, A, Murina, O, Tarnauskaite, Z, Wessel, S R, Zlatanou, A, Vernet, A, von Kriegsheim, A, Mottram, R M A, Logan, C V, Bye, H, Li, Y, Brean, A, Maddirevula, S, Challis, R C, Skouloudaki, K, Almoisheer, A, Alsaif, H S, Amar, A, Prescott, N J, Bober, M, Duker, A, Faqeih, E, Seidahmed, M Z, Tala, S A, Alswaid, A, Ahmed, S, Al-Aama, J Y, Altmuller, J, Al Balwi, M, Brady, A F, Chessa, L, Cox, H, Fischetto, R, Heller, R, Henderson, B D, Hobson, E, Nurnberg, P, Percin, E F, Peron, A, Spaccini, L, Quigley, A J, Thakur, S, Wise, C A, Yoon, G, Alnemer, M, Yigit, G, Taylor, A M R, Reijns, M A M, Simpson, M A, Cortez, D, Alkuraya, F S, Mathew, C G, Jackson, A P & Stewart, G S 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 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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