The HNRNPD protein from DNA repair to immune response

Genomic instability is one of the hallmarks of cancer crucial for tumor development and progression. Among the various types of DNA damage, DNA double strand breaks (DSBs) are the most toxic lesions for the genetic material, leading severe consequences on cell viability predisposing to cancer transformation. In order to preserve the genome integrity, two main pathways, homologous recombination (HR) and non-homologous end joining (NHEJ) are activated to repair DSBs. Recent studies highlight a novel role for the RNA:DNA hybrids (R-loop) as crucial regulators of transcription termination, innate immune activation and DNA repair. Moreover, the aberrant regulation of R-loop was we demonstrated that depletion of heterogeneous nuclear ribonucleoprotein D protein (HNRNPD), also known as AUF1, impairs the homologous recombination by inhibiting DNA-end resection, through the R-loop increase onto damaged sites. Here, we explored the potential role of AUF1 protein dysfunction as a bridge between DNA repair and immune response, proposing it as a novel strategy for cancer therapy. Firstly, we demonstrated how Hela knockout AUF1 cells (AUF1 KO) showed an increase of cytoplasmic R-loop formation in response to camptothecin treatment (CPT), respect to control, through Cyto-DRIP and immunofluorescence assay. Furthermore, we observed enhanced micronuclei in AUF1 KO cells, upon DNA damage, leading to the activation of cGAS-STING signaling pathway, triggering the expression of interferon (IFN) 3. The overexpression of RNase H1 NLS, which is expressed exclusively in the nucleus, reduced the activation of cGAS-STING signaling pathway. Overall, our data suggest novel functions of AUF1 in genome stability and immune response activation, through the R- loop regulation, in response to DSBs. To study the molecular functions of AUF1 will provide a better understanding of cancer-immune biology and will impact the development of new approaches for the prevention and treatment of cancer, proposing AUF1 as a plausible novel target for molecular therapeutics.