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Impaired protein hydroxylase activity causes replication stress and developmental abnormalities in humans

Authors :
Fletcher, Sally C.
Hall, Charlotte
Kennedy, Tristan J.
Pajusalu, Sander
Wojcik, Monica H.
Boora, Uncaar
Li, Chan
Oja, Kaisa Teele
Hendrix, Eline
Westrip, Christian A.E.
Andrijes, Regina
Piasecka, Sonia K.
Singh, Mansi
Asrag, Mohammed E. El-
Ptasinska, Anetta
Tillmann, Vallo
Higgs, Martin R.
Carere, Deanna A.
Beggs, Andrew D.
Pappas, John
Rabin, Rachel
Smerdon, Stephen J.
Stewart, Grant S.
Ounap, Katrin
Coleman, Mathew L.
Source :
Journal of Clinical Investigation. April 1, 2023, Vol. 133 Issue 7
Publication Year :
2023

Abstract

Although protein hydroxylation is a relatively poorly characterized posttranslational modification, it has received significant recent attention following seminal work uncovering its role in oxygen sensing and hypoxia biology. Although the fundamental importance of protein hydroxylases in biology is becoming clear, the biochemical targets and cellular functions often remain enigmatic. JMJD5 is a 'JmjC-only' protein hydroxylase that is essential for murine embryonic development and viability. However, no germline variants in JmjC-only hydroxylases, including JMJD5, have yet been described that are associated with any human pathology. Here we demonstrate that biallelic germline JMJD5 pathogenic variants are deleterious to JMJD5 mRNA splicing, protein stability, and hydroxylase activity, resulting in a human developmental disorder characterized by severe failure to thrive, intellectual disability, and facial dysmorphism. We show that the underlying cellular phenotype is associated with increased DNA replication stress and that this is critically dependent on the protein hydroxylase activity of JMJD5. This work contributes to our growing understanding of the role and importance of protein hydroxylases in human development and disease.<br />Introduction The enzymatic incorporation of a single oxygen atom into an amino acid side chain is a relatively poorly characterized but emerging posttranslational modification (PTM) (1). Seminal work on the [...]

Details

Language :
English
ISSN :
00219738
Volume :
133
Issue :
7
Database :
Gale General OneFile
Journal :
Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsgcl.746858932
Full Text :
https://doi.org/10.1172/JCI152784