Abstract
Collisions between advancing replication forks and elongating transcripts pose a universal threat. During the rapid nuclear division cycles in early Drosophila embryos, coordinating transcription and replication is critical to reduce the risk of collisions. In each cycle, replication begins immediately after mitosis, while transcription starts 3 min later, overlapping replication for the remainder of interphase. We previously showed that transcription depends on Brd4, which forms hubs at active genes. Here, we show that Brd4 persists on mitotic chromosomes as bookmarks of transcriptional activation. Upon anaphase entry, the replication initiation factor Cdc7 forms Brd4-dependent foci that promote early replication in the following interphase. Additionally, Cdc7 activity disperses Brd4 such that post-mitotic transcription occurs only after a new round of Brd4 hub assembly. Early initiation of replication in conjunction with deferred transcription is proposed to allow unimpeded transcriptional elongation behind advancing replication forks. Supporting this, inhibiting Cdc7 delayed replication, stabilized Brd4 bookmarks, and resulted in premature transcription with elongation defects. We propose that Cdc7 triggers a functional switch in Brd4 that enforces temporal ordering of the initiation of replication and transcription, thereby minimizing collisions. This switching process might underlie the widespread correlation between transcriptional activity and early replication.
