Shelterin promotes tethering of late replication origins to telomeres for replication‐timing control

Abstract

DNA replication initiates at many discrete loci on eukaryotic chromosomes, and individual replication origins are regulated under a spatiotemporal program. However, the underlying mechanisms of this regulation remain largely unknown. In the fission yeast , the telomere-binding protein Taz1, ortholog of human TRF1/TRF2, regulates a subset of late replication origins by binding to the telomere-like sequence near the origins. Here, we showed using a/LacI-GFP system that Taz1-dependent late origins were predominantly localized at the nuclear periphery throughout interphase, and were localized adjacent to the telomeres in the G1/S phase. The peripheral localization that depended on the nuclear membrane protein Bqt4 was not necessary for telomeric association and replication-timing control of the replication origins. Interestingly, the shelterin components Rap1 and Poz1 were required for replication-timing control and telomeric association of Taz1-dependent late origins, and this requirement was bypassed by a minishelterin Tpz1-Taz1 fusion protein. Our results suggest that Taz1 suppresses replication initiation through shelterin-mediated telomeric association of the origins at the onset of S phase.

Three-dimensional connectivity and chromatin environment mediate the activation efficiency of mammalian DNA replication origins

“…These membrane-less structures are formed in discrete nuclear zones with a high density of proteins and nucleic acids that establish cooperative interactions between them. For instance, a recent study has revealed how a group of subtelomeric origins in fission yeast are tethered by shelterin components to a local domain enriched in Rif1 and protein phosphatase 1, imposing late replication (Ogawa et al, 2018). The proteins that recognize replication origins, ORC and CDC6, also serve as molecular chaperones capable of attracting and assembling many additional proteins to the factory core, including CDT1, MCM, CDC45, GINS, PCNA, and DNA polymerases that establish multiple contacts between them.…”

The impact of transcription-mediated replication stress on genome instability and human disease

“…In fission yeast, the shelterin complex (also called telosome) is involved in RT regulation of a subgroup of late origins through Rif1. Shelterin can recruit Rif1 on telomeric DNA, as Taz1 does, and also brings late-replicating regions into the proximity of Rif1 (Tazumi et al 2012;Ogawa et al 2018;Kanoh and Ishikawa 2001). Moreover, Rap1 and Poz1 (two members of the shelterin complex) depletion can impact RT in an indirect manner.…”

Preparation for DNA replication: the key to a successful S phase

“…Furthermore, replication origins are active even in heterochromatin where lower accessibility likely makes licensing and origin activation challenging. Some proteins that are not required at origins in other genomic regions, such as ORCA and shelterin , are important for licensing heterochromatin or telomeres. Considering the complexity of the eukaryotic genome, it is remarkable that enough origins are licensed in G1 to ensure the entire genome is usually replicated in S phase with few problems.…”