Different SWI/SNF complexes coordinately promote R-loop- and RAD52-dependent transcription-coupled homologous recombination

The SWI/SNF family of ATP-dependent chromatin remodeling complexes is implicated in multiple DNA damage response mechanisms and frequently mutated in cancer. The BAF, PBAF and ncBAF complexes are three major types of SWI/SNF complexes that are functionally distinguished by their exclusive subunits. Accumulating evidence suggests that double-strand breaks (DSBs) in transcriptionally active DNA are preferentially repaired by a dedicated homologous recombination pathway. We show that different BAF, PBAF and ncBAF subunits promote homologous recombination and are rapidly recruited to DSBs in a transcription-dependent manner. The PBAF and ncBAF complexes promote RNA polymerase II eviction near DNA damage to rapidly initiate transcriptional silencing, while the BAF complex helps to maintain this transcriptional silencing. Furthermore, ARID1A-containing BAF complexes promote RNaseH1 and RAD52 recruitment to facilitate R-loop resolution and DNA repair. Our results highlight how multiple SWI/SNF complexes perform different functions to enable DNA repair in the context of actively transcribed genes.</p

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\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

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‐loops and its chro‐mates: The strange case of dr. jekyll and mr. hyde

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‐transcription conflicts. Finally, we discuss the potential role of several Chro‐ Mates (chromatin modifiers and remodelers) in the likely differentiation between persistent/detri-mental R‐loops and transient/benign R‐loops that assist in various physiological processes relevant for therapeutic interventions