Wdhd1, short for WD repeat and HMG-box DNA binding protein 1, is the mouse ortholog of budding yeast Chromosome Transmission Fidelity 4 (CTF4). It integrates the MCM2-7 helicase and DNA polymerase α/primase complex to initiate DNA replication, playing a crucial role in DNA synthesis [1]. It is also a downstream target of the PI3K/AKT pathway, and its phosphorylation by AKT can induce DNA replication, which may be related to the occurrence of esophageal cancer [2].

In mice, Wdhd1 null allele generated through CRISPR/Cas9-mediated genome editing showed that while Wdhd1 heterozygous mutant mice were normal and fertile, homozygous null mutant embryos had reduced cell proliferation by the gastrulation stage, hampering their growth and viability, indicating its major role in cell proliferation during embryogenesis [1]. In lung adenocarcinoma, knocking out Wdhd1 increased the sensitivity of cisplatin-resistant cells to cisplatin, and WDHD1 overexpression negatively correlated with the overall survival of patients. WDHD1 promoted the ubiquitination of MAPRE2 to lead to cisplatin resistance [3]. In PTEN-inactive triple-negative breast cancer, knockdown of WDHD1 significantly inhibited cell viability, suggesting it could be a potential biomarker or therapeutic target [4].

In conclusion, Wdhd1 is essential for early mouse embryogenesis, especially in cell proliferation. Its dysregulation is associated with multiple cancers such as esophageal cancer, lung adenocarcinoma, and triple-negative breast cancer. Studies using gene knockout mouse models have provided valuable insights into its functions and potential as a therapeutic target in these disease areas.