Walking a tightrope: The complex balancing act of R-loops in genome stability.

Genomic instability is an important driver of ageing. The accumulation of DNA damage is believed to contribute to ageing by inducing cell death, senescence and tissue dysfunction. However, emerging evidence shows that inflammation is another major consequence of DNA damage. Inflammation is a hallmark of ageing and the driver of multiple age-related diseases. Here, we review the evidence linking DNA damage, inflammation and ageing, highlighting how premature ageing syndromes are associated with inflammation. We discuss the mechanisms by which DNA damage induces inflammation, such as through activation of the cGAS-STING axis and NF-κB activation by ATM. The triggers for activation of these signalling cascades are the age-related accumulation of DNA damage, activation of transposons, cellular senescence and the accumulation of persistent R-loops. We also discuss how epigenetic changes triggered by DNA damage can lead to inflammation and ageing via redistribution of heterochromatin factors. Finally, we discuss potential interventions against age-related inflammation. 

DNA damage and repair in age-related inflammation

Genomic instability and inflammation are intricately connected hallmark features of cancer. DNA repair defects due to BRCA1/2 mutation instigate immune signaling through the cGAS/STING pathway. The subsequent inflammatory signaling provides both tumor-suppressive as well as tumor-promoting traits. To prevent clearance by the immune system, genomically instable cancer cells need to adapt to escape immune surveillance. Currently, it is unclear how genomically unstable cancers, including BRCA1/2-mutant tumors, are rewired to escape immune clearance. Here, we summarize the mechanisms by which genomic instability triggers inflammatory signaling and describe adaptive mechanisms by which cancer cells can 'fly under the radar' of the immune system. Additionally, we discuss how therapeutic activation of the immune system may improve treatment of genomically instable cancers. 

http://www.cell.com/article/S240580332100251X/pdf

When breaks get hot: inflammatory signaling in BRCA1/2-mutant cancers

Giordano et al. establish human AGS iPSC-based models of TREX1 or RNASEH2B deficiencies. They uncover DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes that can be uncoupled from aberrant type I IFN responses and identify novel targets to curtail AGS neuroinflammation.

/pdf/dna-damage-contributes-to-neurotoxic-inflammation-in-aicardi-2nnv20gw.pdf

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes

R-loops are RNA–DNA-hybrid-containing nucleic acids with important cellular roles. Deregulation of R-loop dynamics can lead to DNA damage and genome instability1, which has been linked to the action of endonucleases such as XPG2–4. However, the mechanisms and cellular consequences of such processing have remained unclear. Here we identify a new population of RNA–DNA hybrids in the cytoplasm that are R-loop-processing products. When nuclear R-loops were perturbed by depleting the RNA–DNA helicase senataxin (SETX) or the breast cancer gene BRCA1 (refs. 5–7), we observed XPG- and XPF-dependent cytoplasmic hybrid formation. We identify their source as a subset of stable, overlapping nuclear hybrids with a specific nucleotide signature. Cytoplasmic hybrids bind to the pattern recognition receptors cGAS and TLR3 (ref. 8), activating IRF3 and inducing apoptosis. Excised hybrids and an R-loop-induced innate immune response were also observed in SETX-mutated cells from patients with ataxia oculomotor apraxia type 2 (ref. 9) and in BRCA1-mutated cancer cells10. These findings establish RNA–DNA hybrids as immunogenic species that aberrantly accumulate in the cytoplasm after R-loop processing, linking R-loop accumulation to cell death through the innate immune response. Aberrant R-loop processing and subsequent innate immune activation may contribute to many diseases, such as neurodegeneration and cancer. RNA–DNA hybrids are immunogenic species that can aberrantly accumulate in the cytoplasm after R-loop processing, linking R-loop accumulation to cell death through the innate immune response. 

R-loop-derived cytoplasmic RNA–DNA hybrids activate an immune response

How DNA damage leads to chronic inflammation and tissue degeneration with aging remains to be fully resolved. Here, we show that DNA damage leads to cellular senescence, fibrosis, loss-of-tissue ar...

Alexandros Zafeiropoulos

Papers

R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage.