Abstract
Replication of chromosome DNA is an essential step for inheritance of genetic information through generations. DNA replication initiates from distinct loci, replication origins, on the chromosome. Each replication origin is activated at distinct time during S phase through ordered assembly of replication factors. Chromatin structures are considered to be involved in regulation of replication timing, although the mechanism has not been elucidated. We have studied regulation of replication initiation by cell cycle and chromatin structures in fission yeast, which has similar chromatin organizations with multi-cellular organisms. Replication origins in heterochromatic pericentromere and the silent mating-type locus (mat) replicate early S phase, whereas subtelomeric heterochromatin replicates very late despite of highly clustered pre-RCs.
We found that the heterochromatin protein (HP1/Swi6) stimulates the early replication at pericentromere and the mat locus, by recruiting DDK (Dbf4/Dfp1-dependent kinase) through the direct interaction with Dfp1. Loading of replication factor Sld3, which depends on DDK, is stimulated. This step is required for a CDK-dependent assembly of GINS and Cdc45. In contrast, subtelomeric heterochromatin replicates very late in S phase despite of the presence of HP1, suggesting replication is repressed by some mechanism specific to telomeres. Indeed, deletion of taz1+, which encodes a telomere repeat binding protein homologous to human TRF1/hTRF2, results in very early replication of subtelomeres. Rif1 but not Rap1, both bind to the telomere depending on Taz1, is required for the repression. Interestingly, Taz1, Rap1 and Rif1 are also involved in repression of euchromatic late/dormant origins. These results imply that the existence of a global mechanism for regulation of replication.
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