Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability

Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.</p

R‐loops and its chro‐mates

Since their discovery, R‐loops have been associated with both physiological and pathological functions that are conserved across species. R‐loops are a source of replication stress and genome instability, as seen in neurodegenerative disorders and cancer. In response, cells have evolved pathways to prevent R‐loop accumulation as well as to resolve them. A growing body of evidence correlates R‐loop accumulation with changes in the epigenetic landscape. However, the role of chromatin modification and remodeling in R‐loops homeostasis remains unclear. This review covers various mechanisms precluding R‐loop accumulation and highlights the role of chromatin modifiers and remodelers in facilitating timely R‐loop resolution. We also discuss the enigmatic role of RNA:DNA hybrids in facilitating DNA repair, epigenetic landscape and the potential role of replication fork preservation pathways, active fork stability and stalled fork protection pathways, in avoiding replication‐transc

R\xe2\x80\x90loops and its chro\xe2\x80\x90mates

Since their discovery, R\xe2\x80\x90loops have been associated with both physiological and pathological functions that are conserved across species. R\xe2\x80\x90loops are a source of replication stress and genome instability, as seen in neurodegenerative disorders and cancer. In response, cells have evolved pathways to prevent R\xe2\x80\x90loop accumulation as well as to resolve them. A growing body of evidence correlates R\xe2\x80\x90loop accumulation with changes in the epigenetic landscape. However, the role of chromatin modification and remodeling in R\xe2\x80\x90loops homeostasis remains unclear. This review covers various mechanisms precluding R\xe2\x80\x90loop accumulation and highlights the role of chromatin modifiers and remodelers in facilitating timely R\xe2\x80\x90loop resolution. We also discuss the enigmatic role of RNA:DNA hybrids in facilitating DNA repair, epigenetic landscape and the potential role of replication fork preservation pathways, active fork stability and stalled fork protection pathways, in avoiding replication\xe2\x80\x90transcription conflicts. Finally, we discuss the potential role of several Chro\xe2\x80\x90 Mates (chromatin modifiers and remodelers) in the likely differentiation between persistent/detri-mental R\xe2\x80\x90loops and transient/benign R\xe2\x80\x90loops that assist in various physiological processes relevant for therapeutic interventions.</p

Exploring the cost-effectiveness of high versus low perioperative fraction of inspired oxygen in the prevention of surgical site infections among abdominal surgery patients in three low- and middle-income countries

Background: This study assessed the potential cost-effectiveness of high (80–100%) vs low (21–35%) fraction of inspired oxygen (FiO2) at preventing surgical site infections (SSIs) after abdominal surgery in Nigeria, India, and South Africa. Methods: Decision-analytic models were constructed using best available evidence sourced from unbundled data of an ongoing pilot trial assessing the effectiveness of high FiO2, published literature, and a cost survey in Nigeria, India, and South Africa. Effectiveness was measured as percentage of SSIs at 30 days after surgery, a healthcare perspective was adopted, and costs were reported in US dollars ($). Results: High FiO2 may be cost-effective (cheaper and effective). In Nigeria, the average cost for high FiO2 was$216 compared with $222 for low FiO2 leading to a −$6 (95% confidence interval [CI]: −$13 to −$1) difference in costs. In India, the average cost for high FiO2 was $184 compared with$195 for low FiO2 leading to a −$11 (95$15 to −$6) difference in costs. In South Africa, the average cost for high FiO2 was$1164 compared with $1257 for low FiO2 leading to a −$93 (95% CI: −$132 to −$65) difference in costs. The high FiO2 arm had few SSIs, 7.33% compared with 8.38% for low FiO2, leading to a −1.05 (95% CI: −1.14 to −0.90) percentage point reduction in SSIs. Conclusion: High FiO2 could be cost-effective at preventing SSIs in the three countries but further data from large clinical trials are required to confirm this