Deficiency in the nuclear‐related factor erythroid 2 transcription factor ( N rf1) leads to genetic instability

Nuclear factor erythroid‐derived 2‐related factor 1 ( N rf1) regulates cellular stress response genes, and has also been suggested to play a role in other cellular processes. We previously demonstrated that hepatocyte‐specific deletion of N rf1 in mice resulted in spontaneous apoptosis, inflammation, and development of liver tumors. Here, we showed that both fibroblasts derived from N rf1 null mouse embryos and fibroblasts expressing a conditional N rf1 allele showed increased micronuclei and formation of abnormal nuclei. Lentiviral sh RNA ‐mediated knockdown of N rf1 in SAOS –2 cells also resulted in increased micronuclei, abnormal mitosis and multi‐nucleated cells. Metaphase analyses showed increased aneuploidy in N rf1 −/− embryonic fibroblasts. Nuclear defects in Nrf1‐deficient cells were associated with decreased expression of various genes encoding kinetochore and mitotic checkpoint proteins. Our findings suggest that N rf1 may play a role in maintaining genomic integrity, and that N rf1 dysregulation may induce tumorigenesis.