Control of replication timing by a transcriptional silencer.

Eukaryotic DNA replication starts at many origins. Some origins are used early in S phase, while others are programmed to fire later. In general, late replication is correlated with transcriptional inactivity and with location near the nuclear periphery. However, the mechanisms that determine replication timing are unclear, and the cause-and-effect relationship between late replication, transcriptional inactivity, and location at the nuclear periphery is unknown. Using budding yeast, we show that a transcriptional silencer, HMR-E, can reset the time of initiation of ARS305 from early to late. This resetting requires Sir proteins, which are silencers of transcription. Resetting can also be achieved by targeting Sir4 to ARS305. HMR-E sequences and targeted Sir4, both of which cause late replication of ARS305, also cause transcriptional silencing of the nearby APA1 gene. Sir proteins are sufficient to reprogram an origin from early to late; that is, Sir proteins are a cause of late replication. Presumably, the tight chromatin structure promoted by Sir proteins favors both transcriptional inactivity and late replication.