NT5M-mediated R-loop stabilization promotes clear cell renal cell carcinoma progression

Clear cell renal cell carcinoma (ccRCC) has been supposed as one of the most world-widely common tumors accompanied with high incidence and mortality. R-loops are the unique structures in mediating genomic stability and gene expression. It is of great significant to explore the underlying relationship between R-loops and ccRCC progression which contributing to the clinical therapy. This work investigates the interactions between 5',3'-nucleotidase, mitochondrial (NT5M) and R-loops in the process of DNA damage and tumor progression. It was confirmed that NT5M could affect the ubiquitination of RNA helicase DDX5 through ubiquitinase USP7, further promote the degradation of DDX5 protein, subsequently result in the abnormal accumulation of R-loop at ATM promoter site which inducing the DNA damage and tumor inhibition. NT5M knockdown inhibited the proliferation, invasion and migration of ccRCC cells both in vitro and in vivo, which was further confirmed through the treatment of mitoxantrone, the potential NT5M inhibitor. These findings enhance the knowledge of ccRCC pathogenesis and identify new molecular mechanism for therapeutic intervention.