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Updated: Aug 9, 2025
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Examination of Proteins Bound to Nascent DNA in Mammalian Cells Using BrdU-ChIP-Slot-Western Technique
Published on: January 14, 2016
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Impaired protein hydroxylase activity causes replication stress and developmental abnormalities in humans
Sally C Fletcher1, Charlotte Hall1, Tristan J Kennedy1
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
The Journal of Clinical Investigation
|February 16, 2023
Summary
Pathogenic variants in JMJD5, a protein hydroxylase, cause a human developmental disorder by impairing its activity. This leads to increased DNA replication stress, impacting embryonic development and viability.
Area of Science:
- Biochemistry
- Genetics
- Developmental Biology
Background:
- Protein hydroxylation is a crucial posttranslational modification involved in oxygen sensing and hypoxia.
- JMJD5, a JmjC-only protein hydroxylase, is vital for embryonic development, but its role in human pathology was unknown.
Purpose of the Study:
- To investigate the role of JMJD5 in human development and disease.
- To identify the molecular mechanisms underlying JMJD5-associated disorders.
Main Methods:
- Analysis of biallelic germline JMJD5 pathogenic variants in patients.
- Assessment of JMJD5 mRNA splicing, protein stability, and hydroxylase activity.
- Investigation of cellular phenotypes, including DNA replication stress.
Main Results:
- Biallelic germline JMJD5 variants impair splicing, stability, and activity, causing a developmental disorder.
- The disorder is characterized by failure to thrive, intellectual disability, and facial dysmorphism.
- JMJD5 hydroxylase activity is critical for preventing DNA replication stress.
Conclusions:
- Germline JMJD5 variants cause a human developmental disorder through loss of hydroxylase activity.
- JMJD5 plays a critical role in preventing DNA replication stress during development.
- This study highlights the importance of protein hydroxylases in human development and disease.
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