RRC ID 79119
Author Chisada S, Ohtsuka K, Fujiwara M, Yoshida M, Matsushima S, Watanabe T, Karita K, Ohnishi H.
Title A rad50 germline mutation induces tumorigenesis and ataxia-telangiectasia phenotype in a transparent medaka model.
Journal PLoS One
Abstract The MRE11A-RAD50-NBS1 complex activates the ataxia-telangiectasia mutated (ATM) pathway and plays a central role in genome homeostasis. The association of RAD50 mutations with disease remains unclear; hence, we adopted a medaka rad50 mutant to demonstrate the significance of RAD50 mutation in pathogenesis using the medaka as an experimental animal. A 2-base pair deletion in the rad50 gene was introduced into transparent STIII medaka using the CRISPR/Cas9 system. The mutant was analyzed histologically for tumorigenicity and hindbrain quality, as well as for swimming behavior, to compare with existing ATM-, MRE11A-, and NBS1-mutation-related pathology. Our results revealed that the medaka rad50 mutation concurrently reproduced tumorigenesis (8 out of 10 rad50Δ2/+ medaka), had a decrease in median survival time (65.7 ± 1.1 weeks in control vs. 54.2 ± 2.6 weeks in rad50Δ2/+ medaka, p = 0.001, Welch's t-test), exhibited semi-lethality in rad50Δ2/Δ2 medaka and most of the major ataxia-telangiectasia phenotypes, including ataxia (rheotaxis ability was lower in rad50Δ2/+ medaka than in the control, Mann-Whitney U test, p < 0.05), and telangiectasia (6 out of 10 rad50Δ2/+ medaka). The fish model may aid in further understanding the tumorigenesis and phenotype of ataxia-telangiectasia-related RAD50 germline mutations and in developing novel therapeutic strategies against RAD50 molecular disorders.
Volume 18(4)
Pages e0282277
Published 2023-1-1
DOI 10.1371/journal.pone.0282277
PII PONE-D-22-32016
PMID 37098078
PMC PMC10129005
MeSH Animals Ataxia Telangiectasia* / genetics Ataxia Telangiectasia Mutated Proteins / genetics Ataxia Telangiectasia Mutated Proteins / metabolism Carcinogenesis Cell Cycle Proteins / metabolism Cell Transformation, Neoplastic DNA Damage Germ-Line Mutation Mutation Oryzias* / genetics Oryzias* / metabolism Phenotype Protein Serine-Threonine Kinases / metabolism Tumor Suppressor Proteins / genetics
Medaka STII