Senataxin and R-loops homeostasis: multifaced implications in carcinogenesis

Abstract R-loops are inherent byproducts of transcription consisting of an RNA:DNA hybrid and a displaced single-stranded DNA. These structures are of key importance in controlling numerous physiological processes and their homeostasis is tightly controlled by the activities of several enzymes deputed to process R-loops and prevent their unproper accumulation. Senataxin (SETX) is an RNA/DNA helicase which catalyzes the unwinding of RNA:DNA hybrid portion of the R-loops, promoting thus their resolution. The key importance of SETX in R-loops homeostasis and its relevance with pathophysiological events is highlighted by the evidence that gain or loss of function SETX mutations underlie the pathogenesis of two distinct neurological disorders. Here, we aim to describe the potential impact of SETX on tumor onset and progression, trying to emphasize how dysregulation of this enzyme observed in human tumors might impact tumorigenesis. To this aim, we will describe the functional relevance of SETX in regulating gene expression, genome integrity, and inflammation response and discuss how cancer-associated SETX mutations might affect these pathways, contributing thus to tumor development.