Humanized yeast ORC drives R-loop dependent transcription-replication conflicts and global gene dysregulation.

Pervasive, unscheduled humanized ORC binding in compact yeast drives R-loop–linked transcription-replication conflicts and disrupts expression across thousands of genes.

• Why it matters: ORC normally helps coordinate replication with transcription, but how human-like ORC promoter binding in compact genomes affects genome-wide transcriptional stability is unclear.
• What they did: In a mutant yeast model recapitulating human ORC sequence-agnostic promoter binding, the authors mapped ORC-driven R-loop conflicts and tested promoter replacement with a replication origin sequence.
• The result: Origin substitution preserved robust transcription, and its promoter-like activity depended on origin-encoded nucleosome-depleted regions, while +1 nucleosome repositioning shifted transcription start sites.

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