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ABSTRACT
Chromatin structures are transmitted to daughter cells through a complex system of nucleosome disassembly and re-assembly at the advancing replication forks. However, the role of replication pausing in the transmission and perturbation of chromatin structures has not been addressed. RRM3 encodes a DNA helicase, which facilitates replication at sites covered with non-histone protein complexes (tRNA genes, active gene promoters, telomeres) in Saccharomyces cerevisiae. In this report we show that the deletion of RRM3 reduces the frequency of epigenetic conversions in the subtelomeric regions of the chromosomes. This phenotype is strongly dependent on 2 histone chaperones, CAF-I and ASF1, which are involved in the reassembly of nucleosomes behind replication forks, but not on the histone chaperone HIR1. We also show that the deletion of RRM3 increases the spontaneous mutation rates in conjunction with CAF-I and ASF1, but not HIR1. Finally, we demonstrate that Rrm3p and CAF-I compete for the binding to the DNA replication clamp PCNA (Proliferating Cell Nuclear Antigen). We propose that the stalling of DNA replication predisposes to epigenetic conversions and that RRM3 and CAF-I play key roles in this process.
Abbreviations
| ASF1 | = | Anti-Silencing Factor 1 |
| CAF-I | = | Chromatin Assembly Factor I |
| ChIP | = | Chromatin Immuno-Precipitation |
| FACT | = | Facilitator of Activated Transcription on Chromatin templates |
| PCNA | = | Proliferating Cell Nuclear Antigen |
| PEV | = | Position-Effect Variegation |
| PIP | = | PCNA Interacting Peptide |
| RFB | = | Replication Fork Boundary |
| TPE | = | Telomere Position Effect |
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
We thank Dr. Kaufman, Dr. Basrai, Dr. Labib, Dr. Zakian, Dr. Kolodner and Dr. Bielinsky for the generous donation of strains and plasmids.
Funding
This study is supported by a Discovery Grant to KY by the National Science and Engineering Research Council (NSERC) of Canada (grant # RGPIN-2015-06727). BW is supported by an Ontario Government Studentship (OGS).