范可尼贫血（FA）是一种具有毁灭性的遗传性疾病，急需新型治疗策略。它由FA通路中至少22个基因之一的突变引起，其特征是发育异常、骨髓衰竭和癌症易感性。FA通路在损伤DNA的高效修复中起到重要作用，包括修复DNA的串跨联（ICL）。最近的研究表明，甲醛是FA病理生理学中DNA损伤的最终内源性原因。甲醛可以通过在双链DNA的相对链之间诱导形成共价连接，形成DNA加合物和ICL。在本研究中，我们通过扰乱ube2t或fancd2基因在斑马鱼中构建了FA的疾病模型，结果显示出引人注目的雌雄转化表型。由于甲醛由酒精脱氢酶5（ADH5）解毒排出体外，我们生成了fancd2-/-/adh5-/-斑马鱼。我们观察到其身体体积减小和成熟精子数量较少，与野生型或单一敲除斑马鱼相比。为评估ADH5的增加活性是否会影响FA表型，我们在fancd2-/-斑马鱼中过表达人类ADH5。由于ADH5的过表达，观察到了精子发生过程的部分恢复。我们的结果表明，ADH5酶激活剂有潜在用于甲醛清除和治疗FA的治疗措施。© 2023. The Author(s), under exclusive licence to Springer Nature B.V.

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.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.Our results suggest potential utility of an ADH5 enzyme activator as a therapeutic measure for the clearance of formaldehyde and treatment of FA.© 2023. The Author(s), under exclusive licence to Springer Nature B.V.