DTYMK is essential for genome integrity and neuronal survival.
DTYMK is essential for genome integrity and neuronal survival.
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DOI：
10.1007/s00401-021-02394-0
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发表时间：
2022-03
影响因子：
12.7
通讯作者：
Stumpel CTRM
中科院分区：
文献类型：
--
作者：
Vanoevelen JM;Bierau J;Grashorn JC;Lambrichs E;Kamsteeg EJ;Bok LA;Wevers RA;van der Knaap MS;Bugiani M;Frisk JH;Colnaghi R;O'Driscoll M;Hellebrekers DMEI;Rodenburg R;Ferreira CR;Brunner HG;van den Wijngaard A;Abdel-Salam GMH;Wang L;Stumpel CTRM
核苷酸代谢是一个复杂的途径，调节重要的细胞过程，如核酸合成，DNA修复和增殖。这项研究表明，DNA结构单元之一dTTP的生物合成受损，会导致严重的早发性神经退行性疾病。在这里，我们描述了两个不相关的儿童与双等位基因变异的DTYMK，编码dTMPK，催化倒数第二步dTTP生物合成。受影响的儿童表现出严重的小头畸形和生长迟缓，神经发育最少。脑影像学检查显示严重的脑萎缩和基底神经节消失。在受影响个体的细胞中，dTMPK酶活性极低，沿着DNA复制受损。此外，我们产生了dtyphin突变斑马鱼，复制这种表型的小头畸形，神经元细胞死亡和早期致死。增加核糖核苷酸掺入的基因组中，以及受损的DNA损伤的反应中观察到的dtyplatin突变斑马鱼，提供新的病理生理学的见解。非常值得注意的是，由于dTTP合成的代谢途径被完全阻断，这种缺陷是可行的，因为不能产生DNA的必需组分。总之，通过在多种模型中结合遗传和生化方法，我们确定DTYMK功能丧失是严重的出生后神经退行性疾病的原因，并强调了dTTP合成在维持基因组稳定性和神经元存活中的重要性质。在线版本包含补充材料，可通过10.1007/s 00401 -021-02394-0获得。
Nucleotide metabolism is a complex pathway regulating crucial cellular processes such as nucleic acid synthesis, DNA repair and proliferation. This study shows that impairment of the biosynthesis of one of the building blocks of DNA, dTTP, causes a severe, early-onset neurodegenerative disease. Here, we describe two unrelated children with bi-allelic variants in DTYMK, encoding dTMPK, which catalyzes the penultimate step in dTTP biosynthesis. The affected children show severe microcephaly and growth retardation with minimal neurodevelopment. Brain imaging revealed severe cerebral atrophy and disappearance of the basal ganglia. In cells of affected individuals, dTMPK enzyme activity was minimal, along with impaired DNA replication. In addition, we generated dtymk mutant zebrafish that replicate this phenotype of microcephaly, neuronal cell death and early lethality. An increase of ribonucleotide incorporation in the genome as well as impaired responses to DNA damage were observed in dtymk mutant zebrafish, providing novel pathophysiological insights. It is highly remarkable that this deficiency is viable as an essential component for DNA cannot be generated, since the metabolic pathway for dTTP synthesis is completely blocked. In summary, by combining genetic and biochemical approaches in multiple models we identified loss-of-function of DTYMK as the cause of a severe postnatal neurodegenerative disease and highlight the essential nature of dTTP synthesis in the maintenance of genome stability and neuronal survival. The online version contains supplementary material available at 10.1007/s00401-021-02394-0.
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影响因子：
4
作者：
Ali, M;Highet, LJ;Crow, YJ
通讯作者：
Crow, YJ
影响因子：
13.8
作者：
Cerritelli SM;Crouch RJ
通讯作者：
Crouch RJ
影响因子：
30.8
作者：
Bourdon, Alice;Minai, Limor;Rotig, Agnes
通讯作者：
Rotig, Agnes
从DNA中酶促去除核糖核苷酸对于哺乳动物的基因组完整性和发育至关重要。
影响因子：
64.5
作者：
Reijns MA;Rabe B;Rigby RE;Mill P;Astell KR;Lettice LA;Boyle S;Leitch A;Keighren M;Kilanowski F;Devenney PS;Sexton D;Grimes G;Holt IJ;Hill RE;Taylor MS;Lawson KA;Dorin JR;Jackson AP
通讯作者：
Jackson AP
影响因子：
3.4
作者：
Meroni A;Mentegari E;Crespan E;Muzi-Falconi M;Lazzaro F;Podestà A
通讯作者：
Podestà A