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A R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes

ABSTRACT: Nuclear organization has emerged as a critical player in the control of genomic processes, including transcription. In this context, nuclear pore complexes (NPCs) have increasingly recognized interactions with the genome, as exemplified in yeast, where they bind inducible genes and damaged genomic regions, positively impacting their fate. To investigate the pathways fostering chromatin association with NPCs, we have combined genome-wide approaches with live imaging of individually-tagged model loci. Strikingly, ChIP-seq analyses of NPC-bound genes revealed a strong correlation between pore association and the propensity to accumulate co-transcriptional R-loops, which are genotoxic structures forming through hybridization of nascent RNAs with their DNA templates. Manipulating cis- or trans-acting regulators of hybrid formation further demonstrated that R-loop accumulation per se, rather than high transcription or R-loop-associated genetic instability, is the primary trigger for relocation to NPCs. Mechanistically, R-loop-dependent repositioning involves the recognition of displaced ssDNA moieties by the ssDNA-binding protein RPA, and SUMO-dependent interactions between RPA and NPC-associated factors. Preventing R-loop-dependent NPC localization leads to lethality, while permanent NPC tethering of a model hybrid-prone sequence attenuates R-loop-dependent genetic instability. Remarkably, this novel relocation pathway involves similar molecular factors as those required for the association of stalled replication forks or eroded telomeres with NPCs, suggesting the existence of convergent mechanisms for sensing transcriptional and genotoxic stresses.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE225324 | GEO | 2023/08/21

REPOSITORIES: GEO

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Rtt105 promotes DNA replication by functioning as an RPA chaperone

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