The proper coordination of transcription with DNA replication and repair is central for genomic stability. We investigate how the INO80C chromatin remodeling enzyme might coordinate these genomic processes. We find that INO80C co-localizes with the origin recognition complex (ORC) at yeast replication origins and is bound to replication initiation sites in mouse embryonic stem cells (mESCs). In yeast, INO80C recruitment requires origin sequences but does not require ORC, suggesting that recruitment is independent of pre-replication complex assembly. In both yeast and ESCs, INO80C co-localizes at origins with Mot1 and NC2 transcription factors, and genetic studies suggest that they function together to promote genome stability. Interestingly, nascent transcript sequencing demonstrates that INO80C and Mot1 prevent pervasive transcription through origin sequences, and absence of these factors leads to formation of new DNA double-strand breaks. We propose that INO80C and Mot1/NC2 function through distinct pathways to limit origin transcription, maintaining genomic stability.

转录与 DNA 复制和修复的适当协调对于基因组稳定性至关重要。我们研究 INO80C 染色质重塑酶如何协调这些基因组过程。我们发现 INO80C 在酵母复制起点与起源识别复合物 (ORC) 共定位，并与小鼠胚胎干细胞 (mESCs) 中的复制起始位点结合。在酵母中，INO80C 招募需要原始序列但不需要 ORC，这表明招募与复制前复合物组装无关。在酵母和 ESC 中，INO80C 与 Mot1 和 NC2 转录因子共同定位于起源，遗传研究表明它们共同作用以促进基因组稳定性。有趣的是，新生转录本测序表明 INO80C 和 Mot1 通过起源序列阻止普遍转录，并且这些因子的缺失导致新的 DNA 双链断裂的形成。我们建议 INO80C 和 Mot1/NC2 通过不同的途径发挥作用，以限制起源转录，维持基因组稳定性。