Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.
Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.
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DOI：
10.1038/ng.3790
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发表时间：
2017-04
期刊：
影响因子：
30.8
通讯作者：
Stewart GS
中科院分区：
文献类型：
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作者：
Reynolds JJ;Bicknell LS;Carroll P;Higgs MR;Shaheen R;Murray JE;Papadopoulos DK;Leitch A;Murina O;Tarnauskaitė Ž;Wessel SR;Zlatanou A;Vernet A;von Kriegsheim A;Mottram RM;Logan CV;Bye H;Li Y;Brean A;Maddirevula S;Challis RC;Skouloudaki K;Almoisheer A;Alsaif HS;Amar A;Prescott NJ;Bober MB;Duker A;Faqeih E;Seidahmed MZ;Al Tala S;Alswaid A;Ahmed S;Al-Aama JY;Altmüller J;Al Balwi M;Brady AF;Chessa L;Cox H;Fischetto R;Heller R;Henderson BD;Hobson E;Nürnberg P;Percin EF;Peron A;Spaccini L;Quigley AJ;Thakur S;Wise CA;Yoon G;Alnemer M;Tomancak P;Yigit G;Taylor AM;Reijns MA;Simpson MA;Cortez D;Alkuraya FS;Mathew CG;Jackson AP;Stewart GS
为了确保有效的基因组复制，细胞已经进化出许多因子来促进不受干扰的DNA复制，并保护，修复和重新启动受损的叉。在这里，我们确定DONSON作为一种新的分叉保护因子，并报告29例小头侏儒症患者的双等位基因DONSON突变。我们证明，DONSON是一个复制体的组成部分，稳定叉在基因组复制。DONSON的缺失导致由停滞的复制叉的溶核切割引起的严重的复制相关DNA损伤。此外，响应于复制应激的ATR依赖性信号传导在DONSON缺陷细胞中受损，导致检查点活性降低，并增强染色体不稳定性。亚型突变显著降低DONSON蛋白水平并损害患者细胞中的叉稳定性，这与疾病表型的DNA复制缺陷一致。总之，我们确定DONSON突变是小头畸形侏儒症的常见原因，并确定DONSON是哺乳动物DNA复制和基因组稳定性所需的关键复制叉蛋白。
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 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 stabilises forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.