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
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Nat Genet. 2017 Apr;49(4):537-549. doi: 10.1038/ng.3790. Epub 2017 Feb 13.
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.
为确保高效的基因组复制，细胞进化出了众多促进DNA复制不受干扰以及保护、修复和重启受损复制叉的因子。在此，我们鉴定出SON下游邻居（DONSON）作为一种新型的复制叉保护因子，并报告了29例小头畸形侏儒症患者中存在双等位基因DONSON突变。我们证明DONSON是一种复制体成分，在基因组复制过程中稳定复制叉。DONSON缺失会导致因停滞的复制叉的核酸酶切割而产生严重的与复制相关的DNA损伤。此外，在DONSON缺陷细胞中，响应复制应激的ATM和Rad3相关（ATR）依赖性信号传导受损，导致检查点活性降低和染色体不稳定性增强。DONSON的次等位基因突变会大幅降低患者细胞中DONSON蛋白水平并损害复制叉稳定性，这与该疾病表型背后的DNA复制缺陷一致。总之，我们已确定DONSON突变是小头畸形侏儒症的常见病因，并将DONSON确立为哺乳动物DNA复制和基因组稳定性所需的关键复制叉蛋白。
