PUBLICATION

Effects of the major formaldehyde catalyzer ADH5 on phenotypes of fanconi anemia zebrafish model

Authors
Mu, A., Cao, Z., Huang, D., Hosokawa, H., Maegawa, S., Takata, M.
ID
ZDB-PUB-230825-47
Date
2023
Source
Molecular biology reports   50(10): 8385-8395 (Journal)
Registered Authors
Maegawa, Shingo
Keywords
ADH5, ALDH2, FANCD2, Fanconi anemia, Formaldehyde, UBE2T
MeSH Terms
  • Animals
  • DNA Damage
  • DNA Repair
  • Fanconi Anemia*/genetics
  • Female
  • Formaldehyde
  • Humans
  • Male
  • Phenotype
  • Zebrafish*/genetics
(all 10)
PubMed
37615925 Full text @ Mol. Biol. Rep.
Abstract
Background Fanconi anemia (FA) is a devastating hereditary disorder for which we desperately need a novel therapeutic strategy. It is caused by mutations in one of at least 22 genes in the FA pathway and is characterized by developmental abnormalities, bone marrow failure, and cancer predisposition. The FA pathway is required for the efficient repair of damaged DNA, including interstrand cross-links (ICL). Recent studies indicate formaldehyde as an ultimate endogenous cause of DNA damage in FA pathophysiology. Formaldehyde can form DNA adducts as well as ICLs by inducing covalent linkages between opposite strands of double-stranded DNA.
Methods and results In this study, we generated a disease model of FA in zebrafish by disrupting the ube2t or fancd2 gene, which resulted in a striking phenotype of female-to-male sex reversal. Since formaldehyde is detoxified from the body by alcohol dehydrogenase 5 (ADH5), we generated fancd2-/-/adh5-/- zebrafish. We observed a body size reduction and a lower number of mature spermatozoa than wild-type or single knockout zebrafish. To evaluate if increased activity in ADH5 can affect the FA phenotype, we overexpressed human ADH5 in fancd2-/- zebrafish. The progress of spermatogenesis seemed to be partially recovered due to ADH5 overexpression.
Conclusions Our results suggest potential utility of an ADH5 enzyme activator as a therapeutic measure for the clearance of formaldehyde and treatment of FA.
Genes / Markers
Marker Marker Type Name
adh5GENEalcohol dehydrogenase 5
aldh2.1GENEaldehyde dehydrogenase 2 family member, tandem duplicate 1
aldh2.2GENEaldehyde dehydrogenase 2 family member, tandem duplicate 2
fancd2GENEFA complementation group D2
ube2tGENEubiquitin-conjugating enzyme E2T (putative)
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Figures
No images available
Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zf3960
    		Insertion
    zf3961
      		Small Deletion
      zf3962
        		Indel
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        adh5CRISPR2-adh5CRISPR
        fancd2CRISPR2-fancd2CRISPR
        ube2tCRISPR2-ube2tCRISPR
        1 - 3 of 3
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        Fish
        No data available
        Antibodies
        No data available
        Orthology
        Engineered Foreign Genes
        No data available
        Mapping
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        Citation
        Mu, A., Cao, Z., Huang, D., Hosokawa, H., Maegawa, S., Takata, M. (2023) Effects of the major formaldehyde catalyzer ADH5 on phenotypes of fanconi anemia zebrafish model. Molecular biology reports. 50(10):8385-8395.