PUBLICATION
Loss of Brcc3 in Zebrafish Embryos Increases Their Susceptibility to DNA Damage Stress
- Authors
- Wang, Z., Wang, C., Zhai, Y., Bai, Y., Wang, H., Rong, X.
- ID
- ZDB-PUB-241127-30
- Date
- 2024
- Source
- International Journal of Molecular Sciences 25(22): (Journal)
- Registered Authors
- Rong, Xiaozhi, Wang, Caixia
- Keywords
- ATM, Brcc3, CRISPR/Cas9, DNA damage, ETO, UV, p53, zebrafish
- MeSH Terms
-
- Ultraviolet Rays/adverse effects
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Apoptosis/genetics
- DNA Damage*
- Animals
- Embryo, Nonmammalian/metabolism
- DNA Breaks, Double-Stranded
- CRISPR-Cas Systems
- Zebrafish*/embryology
- Zebrafish*/genetics
- Etoposide/pharmacology
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- DNA Repair
- PubMed
- 39596176 Full text @ Int. J. Mol. Sci.
Citation
Wang, Z., Wang, C., Zhai, Y., Bai, Y., Wang, H., Rong, X. (2024) Loss of Brcc3 in Zebrafish Embryos Increases Their Susceptibility to DNA Damage Stress. International Journal of Molecular Sciences. 25(22):.
Abstract
DNA double-strand breaks (DSBs) represent one of the most severe forms of genetic damage in organisms, yet vertebrate models capable of monitoring DSBs in real-time remain scarce. BRCA1/BRCA2-containing complex subunit 3 (BRCC3), also known as BRCC36, functions within various multiprotein complexes to mediate diverse biological processes. However, the physiological role of BRCC3 in vertebrates, as well as the underlying mechanisms that govern its activity, are not well understood. To explore these questions, we generated brcc3-knockout zebrafish using CRISPR/Cas9 gene-editing technology. While brcc3 mutant zebrafish appear phenotypically normal and remain fertile, they exhibit significantly increased rates of mortality and deformity following exposure to DNA damage. Furthermore, embryos lacking Brcc3 display heightened p53 signaling, elevated γ-H2AX levels, and increased apoptosis in response to DNA-damaging agents such as ultraviolet (UV) light and Etoposide (ETO). Notably, genetic inactivation of p53 or pharmacological inhibition of Ataxia-telangiectasia mutated (ATM) activity rescues the hypersensitivity to UV and ETO observed in Brcc3-deficient embryos. These findings suggest that Brcc3 plays a critical role in DNA damage response (DDR), promoting cell survival during embryogenesis. Additionally, brcc3-null mutant zebrafish offer a promising vertebrate model for real-time monitoring of DSBs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping