Sir2 mitigates an intrinsic imbalance in origin licensing efficiency between early- and late-replicating euchromatin

A eukaryotic chromosome relies on the function of multiple spatially distributed DNA replication origins for its stable inheritance. The spatial location of an origin is determined by the chromosomal position of an MCM complex, the inactive form of the DNA replicative helicase that is assembled onto...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2020-06, Vol.117 (25), p.14314-14321
Main Authors: Hoggard, Timothy, Müller, Carolin A., Nieduszynski, Conrad A., Weinreich, Michael, Fox, Catherine A.
Format: Article
Language:English
Subjects:
Attenuation
Biological Sciences
Cell Cycle Proteins - metabolism
Chromosomal Proteins, Non-Histone
Chromosomes
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA helicase
DNA Helicases
DNA Replication
Euchromatin
Euchromatin - metabolism
Genomes
Heredity
Heterochromatin
Histone deacetylase
Licenses
Licensing
Normal distribution
Origins
Replicating
Replication
Replication Origin - genetics
Replication origins
Reproduction (copying)
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - metabolism
Silent Information Regulator Proteins, Saccharomyces cerevisiae - metabolism
Sirtuin 2 - metabolism
Spatial distribution
Yeasts
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Summary:A eukaryotic chromosome relies on the function of multiple spatially distributed DNA replication origins for its stable inheritance. The spatial location of an origin is determined by the chromosomal position of an MCM complex, the inactive form of the DNA replicative helicase that is assembled onto DNA in G1-phase (also known as origin licensing). While the biochemistry of origin licensing is understood, the mechanisms that promote an adequate spatial distribution of MCM complexes across chromosomes are not. We have elucidated a role for the Sir2 histone deacetylase in establishing the normal distribution of MCM complexes across Saccharomyces cerevisiae chromosomes. In the absence of Sir2, MCM complexes accumulated within both early-replicating euchromatin and telomeric heterochromatin, and replication activity within these regions was enhanced. Concomitantly, the duplication of several regions of late-replicating euchromatin were delayed. Thus, Sir2-mediated attenuation of origin licensing within both euchromatin and telomeric heterochromatin established the normal spatial distribution of origins across yeast chromosomes important for normal genome duplication.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2004664117