PUBLICATION
Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish
- Authors
- Semenova, S.A., Nammi, D., Garrett, G.B., Margolin, G., Sinclair, J.L., Maroofian, R., Caldecott, K.W., Burgess, H.A.
- ID
- ZDB-PUB-250518-5
- Date
- 2025
- Source
- Scientific Reports 15: 1704317043 (Journal)
- Registered Authors
- Burgess, Harold
- Keywords
- parp1, xrcc1, Cerebellar development, Zebrafish
- MeSH Terms
-
- Mutation
- DNA Breaks, Single-Stranded
- Cerebellum*/abnormalities
- Cerebellum*/metabolism
- Cerebellum*/pathology
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Gene Knockdown Techniques
- X-ray Repair Cross Complementing Protein 1*/genetics
- X-ray Repair Cross Complementing Protein 1*/metabolism
- Gene Deletion*
- Zebrafish*/genetics
- DNA Repair
- Poly (ADP-Ribose) Polymerase-1*/genetics
- Poly (ADP-Ribose) Polymerase-1*/metabolism
- Animals
- PubMed
- 40379758 Full text @ Sci. Rep.
Citation
Semenova, S.A., Nammi, D., Garrett, G.B., Margolin, G., Sinclair, J.L., Maroofian, R., Caldecott, K.W., Burgess, H.A. (2025) Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish. Scientific Reports. 15:1704317043.
Abstract
Defects in DNA single-strand break repair are associated with neurodevelopmental and neurodegenerative disorders. One such disorder is that resulting from mutations in XRCC1, a scaffold protein that plays a central role in DNA single-strand base repair. XRCC1 is recruited at sites of single-strand breaks by PARP1, a protein that detects and is activated by such breaks and is negatively regulated by XRCC1 to prevent excessive PARP binding and activity. Loss of XRCC1 leads to the toxic accumulation and activity of PARP1 at single-strand breaks leading to base excision repair defects, a mechanism that may underlie pathological changes in patients carrying deleterious XRCC1 mutations. Here, we demonstrate that xrcc1 knockdown impairs development of the cerebellar plate in zebrafish. In contrast, parp1 knockdown alone does not significantly affect neural development, and instead rescues the cerebellar defects observed in xrcc1 mutant larvae. These findings support the notion that PARP1 inhibition may be a viable therapeutic candidate in neurological disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping