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 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 on chromosomal DNA in G1-phase (a.k.a. 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 established the normal spatial distribution of origins across yeast chromosomes required for normal genome duplication. Significance statementIn eukaryotes, multiple DNA replication origins, the sites where new DNA synthesis begins during the process of cell division, must be adequately distributed across chromosomes to maintain normal cell proliferation and genome stability. This study describes a repressive chromatin-mediated mechanism that acts at the level of individual origins to attenuate the efficiency of origin formation. This attenuation is essential for achieving the normal spatial distribution of origins across the chromosomes of the eukaryotic microbe Saccharomyces cerevisiae. While the importance of chromosomal origin distribution to cellular fitness is now widely acknowledged, this study is the first to define a specific chromatin modification that establishes the normal spatial distribution of origins across a eukaryotic genome.