R-loop processing

Definition

Target type: biologicalprocess

A DNA metabolic process that results in the disassembly of R-loops. R-loops are three-stranded nucleic acid structures consisitng of an RNA:DNA heteroduplex and a looped-out non-template strand. Aberrant formation and persistence of R-loops block transcription elongation and cause DNA damage. Mechanisms that resolve R-loops are essential for genome stability. [PMID:27252122, PMID:28790157, PMID:33986538]

R-loop processing is a critical cellular process involving the resolution of R-loops, which are three-stranded DNA structures formed when an RNA transcript hybridizes with its template DNA strand, displacing the non-template strand. These structures can be highly dynamic and are often associated with gene regulation and transcription. However, excessive or persistent R-loop formation can lead to genomic instability, DNA damage, and transcriptional dysregulation.

R-loop processing encompasses several mechanisms that contribute to the removal or repair of R-loops:

**1. RNA Polymerase II (RNAPII) activity:** RNAPII, the primary enzyme responsible for mRNA synthesis, plays a crucial role in R-loop formation. The rate of transcription elongation by RNAPII significantly influences the frequency and persistence of R-loops. In regions of high transcription, R-loops are more likely to form and persist due to the prolonged interaction between the RNA transcript and the template DNA.

**2. RNA processing factors:** A variety of RNA processing factors, including RNA helicases, contribute to the removal of R-loops. RNA helicases, such as Senataxin and DHX9, unwind the RNA-DNA hybrid, disrupting the R-loop structure. These enzymes utilize ATP hydrolysis to drive the separation of the RNA and DNA strands.

**3. DNA repair pathways:** R-loops can block DNA replication and cause DNA damage, leading to the activation of DNA repair pathways. The major DNA repair pathways involved in R-loop processing include homologous recombination (HR) and non-homologous end joining (NHEJ). HR is a high-fidelity repair mechanism that uses a homologous template to accurately repair double-stranded DNA breaks. NHEJ is a less precise mechanism that joins broken DNA ends, often leading to mutations.

**4. Topoisomerases:** Topoisomerases are enzymes that regulate DNA topology, which is the overall shape and structure of DNA. They can remove supercoils and other topological stresses that can accumulate during R-loop formation. Topoisomerases play a critical role in preventing R-loop-induced DNA damage and genomic instability.

**5. Other proteins:** A variety of other proteins, including the RNA-binding protein hnRNPA1 and the histone deacetylase SirT1, have been implicated in R-loop processing. These proteins may contribute to the stability, resolution, or repair of R-loops.

R-loop processing is a highly dynamic process, and the specific mechanisms involved can vary depending on the cellular context and the specific R-loop structure. Dysregulation of R-loop processing can lead to a range of human diseases, including cancer, neurodegenerative disorders, and autoimmune diseases.

The intricate interplay between these different mechanisms ensures the efficient and timely removal of R-loops, maintaining genomic stability and preventing harmful consequences for the cell.'
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Proteins (2)

Compounds (78)