Host: The Japanese Society of Toxicology
Name : The 50th Annual Meeting of the Japanese Society of Toxicology
Date : June 19, 2023 - June 21, 2023
Homologous recombination (HR) is one of major DNA repair pathways and utilizes homologous DNA as a template to accomplish acute, error-less DNA repair. Defects in HR cause chromosome instability, and mutations in genes involved in HR are related to cancer (e.g. Brca2) and genetic disorders (e.g. Blm) in humans. Thus, understanding the mechanisms of HR is critical for therapies for cancer and diseases. Acetaldehyde is one of DNA inter-strand crosslink (ICL)-causing chemicals produced in vivo, and induces DNA damage and cancer in humans. While studies using mice have uncovered critical roles of fanconi-anemia (FA) pathway in ICL repair, roles of HR in ICL repair remain elusive, mostly due to early embryonic lethality of mice with mutations in genes involved in HR. SWSAP1 is a recently identified RAD51 paralog required for efficient HR in mice and humans, and Swsap1 knock-out mice develop normally, though infertile, allowing us to investigate its roles as an HR factor in ICL repair. Here we study Swsap1 Aldh2 double knock-out mice where acetaldehyde accumulates in vivo by ethanol exposure, and revealed that the frequency of micronucleus formation is increased in mouse embryonic fibroblasts (MEFs) and the number of hematopoietic cells in born marrow is reduced. Our results suggest essential roles of SWSAP1, likely HR-mediated repair pathway, in ICL repair even when FA-pathway is active, and provide new insight into mechanisms by which HR maintains chromosome stability and suppress cancer.
