Senataxin regulates cisplatin resistance through an R-loop-mediated mechanism in HPV-associated head and neck cancer

Resistance to cisplatin is a key clinical concern in HPV-independent (HPV−) and HPV-associated (HPV+) head and neck cancer. Upregulation of DNA repair is known to contribute to cisplatin resistance and a major source of endogenous DNA damage are DNA/RNA hybrids, known as R-loops. Following creation of HPV+ and HPV− cisplatin resistant cell lines, RNA-sequencing revealed alterations in the expression of known R-loop regulators. Resistant cells had elevated global R-loop levels and in HPV+ resistant cells there was a corresponding upregulation of the R-loop resolving protein, senataxin. Depletion of senataxin led to increased sensitivity to cisplatin, an increase in DNA damage and elevated R-loops at specific genomic loci. In summary, using an in vitro model of cisplatin resistance, we identified that senataxin modulates sensitivity to cisplatin through an R-loop-mediated mechanism in HPV+ cells. R-loops may represent a potential therapeutic target and warrant further investigation.