Vanoevelen, Jo M, Bierau, Jörgen, Grashorn, Janine C, Lambrichs, Ellen, Kamsteeg, Erik-Jan, Bok, Levinus A, Wevers, Ron A, van der Knaap, Marjo S, Bugiani, Marianna, Frisk, Junmei Hu, Colnaghi, Rita, O’Driscoll, Mark, Hellebrekers, Debby M E I, Rodenburg, Richard, Ferreira, Carlos R, Brunner, Han G, van den Wijngaard, Arthur, Abdel-Salam, Ghada M H, Wang, Liya and Stumpel, Constance T R M (2022) DTYMK is essential for genome integrity and neuronal survival. Acta Neuropathologica. a143 245-262. ISSN 0001-6322

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Abstract

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.

Item Type:	Article
Keywords:	DTYMK, Genome instability, Nucleotide metabolism, Zebrafish, dTMPK
Schools and Departments:	School of Life Sciences > Sussex Centre for Genome Damage and Stability
SWORD Depositor:	Mx Elements Account
Depositing User:	Mx Elements Account
Date Deposited:	10 Jan 2022 08:08
Last Modified:	03 Mar 2022 12:44
URI:	http://sro.sussex.ac.uk/id/eprint/103739

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