| Literature DB >> 28191891 |
John J Reynolds1, Louise S Bicknell2, Paula Carroll2, Martin R Higgs1, Ranad Shaheen3, Jennie E Murray2, Dimitrios K Papadopoulos4, Andrea Leitch2, Olga Murina2, Žygimantė Tarnauskaitė2, Sarah R Wessel5, Anastasia Zlatanou1, Audrey Vernet1, Alex von Kriegsheim2, Rachel M A Mottram1, Clare V Logan2, Hannah Bye6, Yun Li7, Alexander Brean1, Sateesh Maddirevula3, Rachel C Challis2, Kassiani Skouloudaki4, Agaadir Almoisheer3, Hessa S Alsaif3, Ariella Amar6, Natalie J Prescott6, Michael B Bober8, Angela Duker8, Eissa Faqeih9, Mohammed Zain Seidahmed10, Saeed Al Tala11, Abdulrahman Alswaid12, Saleem Ahmed13,14, Jumana Yousuf Al-Aama13,14, Janine Altmüller15, Mohammed Al Balwi16, Angela F Brady17, Luciana Chessa18, Helen Cox19, Rita Fischetto20, Raoul Heller21, Bertram D Henderson22, Emma Hobson23, Peter Nürnberg15, E Ferda Percin24, Angela Peron25,26, Luigina Spaccini25, Alan J Quigley27, Seema Thakur28, Carol A Wise29, Grace Yoon30,31, Maha Alnemer32, Pavel Tomancak4, Gökhan Yigit7, A Malcolm R Taylor1, Martin A M Reijns2, Michael A Simpson6, David Cortez5, Fowzan S Alkuraya3, Christopher G Mathew6,33, Andrew P Jackson2, Grant S Stewart1.
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.Entities:
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Year: 2017 PMID： 28191891 PMCID： PMC5450907 DOI： 10.1038/ng.3790
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330