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FORKHEAD TRANSCRIPTION FACTORS ESTABLISH ORIGIN TIMING AND LONG-RANGE CLUSTERING IN S. CEREVISIAE
We characterized the role of a family of transcription factors called ‘Forkhead’ in replication timing. We showed that Forkheads are required for the establishment of replication origins and recruitment of Cdc45, required for initiation of G1 (growth) phase of the cell cycle. The study was carried out in yeast which is easier to study basic cellular processes, especially genome replication and cell division that are more challenging in humans and even human cell culture.
The replication of eukaryotic chromosomes is organized temporally and spatially within the nucleus through epigenetic regulation of replication origin function. The characteristic initiation timing of specific origins is thought to reflect their chromatin environment or sub-nuclear positioning, however the mechanism remains obscure. Here we show that the yeast Forkhead transcription factors, Fkh1 and Fkh2, are global determinants of replication origin timing. Forkhead regulation of origin timing is independent of local levels or changes of transcription. Instead, we show that Fkh1 and Fkh2 are required for the clustering of early origins and their association with the key initiation factor Cdc45 in G1 phase, suggesting that Fkh1 and Fkh2 selectively recruit origins to emergent replication factories. Fkh1 and Fkh2 bind Fkh-activated origins, and interact physically with ORC, providing a plausible mechanism to cluster origins. These findings add a new dimension to our understanding of the epigenetic basis for differential origin regulation and its connection to chromosomal domain organization.
RELEVANCE TO OC
Forkhead transcription factors play a key role in development and risk for
cancers, including ovarian cancer.
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