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.

Machine learning-based identification of novel hub genes associated with oxidative stress in lupus nephritis: implications for diagnosis and therapeutic targets

“…Although their roles in LN remain incompletely elucidated, we observed that decreased expression of PRODH and TXN2 may contribute to the pathogenesis of LN, suggesting potential therapeutic targets for LN by enhancing the PPAR signalling pathway. Similarly, our study detected SETX, an RNA/DNA helicase crucial for transcription termination and genomic integrity, 55 whose expression levels were significantly upregulated in patients with LN. We speculated that SETX may lead to abnormalities in DNA damage repair and transcriptional regulation, contributing to the pathogenesis of LN.…”

R-Loops in Genome Instability and Cancer

“…Using the energy from ATP hydrolysis, they can unwind the hydrogen-bonded base pairs, creating DNA regions that are accessible to cellular machinery like DNA polymerases or RNA polymerases [105,106]. RNA-DNA helicases, such as Aquarius (AQR) and SETX, are responsible for unwinding and dissociating the RNA-DNA hybrid structure, actively promoting the resolution of R-loops to maintain genomic integrity and facilitating various cellular processes [107][108][109].…”