PUBLICATION
Zebrafish reveal new roles for Fam83f in hatching and the DNA damage-mediated autophagic response
- Authors
- Jones, R.A., Cooper, F., Kelly, G., Barry, D., Renshaw, M.J., Sapkota, G., Smith, J.C.
- ID
- ZDB-PUB-241023-3
- Date
- 2024
- Source
- Open Biology 14: 240194240194 (Journal)
- Registered Authors
- Keywords
- DNA damage, Fam83f, autophagy, development, hatching, zebrafish
- Datasets
- GEO:GSE244291
- MeSH Terms
-
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Humans
- DNA Damage*
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Autophagy*/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Gene Expression Regulation, Developmental
- Gene Knockout Techniques
- Lysosomes/metabolism
- Phosphatidylinositol Phosphates/metabolism
- Embryo, Nonmammalian/metabolism
- Animals
- PubMed
- 39437839 Full text @ Open Biol.
Citation
Jones, R.A., Cooper, F., Kelly, G., Barry, D., Renshaw, M.J., Sapkota, G., Smith, J.C. (2024) Zebrafish reveal new roles for Fam83f in hatching and the DNA damage-mediated autophagic response. Open Biology. 14:240194240194.
Abstract
The FAM83 (Family with sequence similarity 83) family is highly conserved in vertebrates, but little is known of the functions of these proteins beyond their association with oncogenesis. Of the family, FAM83F is of particular interest because it is the only membrane-targeted FAM83 protein. When overexpressed, FAM83F activates the canonical Wnt signalling pathway and binds to and stabilizes p53; it therefore interacts with two pathways often dysregulated in disease. Insights into gene function can often be gained by studying the roles they play during development, and here we report the generation of fam83f knock-out (KO) zebrafish, which we have used to study the role of Fam83f in vivo. We show that endogenous fam83f is most strongly expressed in the hatching gland of developing zebrafish embryos, and that fam83f KO embryos hatch earlier than their wild-type (WT) counterparts, despite developing at a comparable rate. We also demonstrate that fam83f KO embryos are more sensitive to ionizing radiation than WT embryos-an unexpected finding, bearing in mind the previously reported ability of FAM83F to stabilize p53. Transcriptomic analysis shows that loss of fam83f leads to downregulation of phosphatidylinositol-3-phosphate (PI(3)P) binding proteins and impairment of cellular degradation pathways, particularly autophagy, a crucial component of the DNA damage response. Finally, we show that Fam83f protein is itself targeted to the lysosome when overexpressed in HEK293T cells, and that this localization is dependent upon a C' terminal signal sequence. The zebrafish lines we have generated suggest that Fam83f plays an important role in autophagic/lysosomal processes, resulting in dysregulated hatching and increased sensitivity to genotoxic stress in vivo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping