DNA replication initiates at genomic locations known as origins of replication, which, in S. cerevisiae, share a common DNA consensus motif. Despite being virtually nucleosome-free, origins of replication are greatly influenced by the surrounding chromatin state. Here, we show that histone H3 lysine 37 mono-methylation (H3K37me1) is catalyzed by Set1p and Set2p and that it regulates replication origin licensing. H3K37me1 is uniformly distributed throughout most of the genome, but it is scarce at replication origins, where it increases according to the timing of their firing. We find that H3K37me1 hinders Mcm2 interaction with chromatin, maintaining low levels of MCM outside of conventional replication origins. Lack of H3K37me1 results in defective DNA replication from canonical origins while promoting replication events at inefficient and non-canonical sites. Collectively, our results indicate that H3K37me1 ensures correct execution of the DNA replication program by protecting the genome from inappropriate origin licensing and spurious DNA replication.
The Kouzarides laboratory is supported by Cancer Research UK (grants RG72100 and RG96894) and core support from the Wellcome Trust (core grant WT203144) and Cancer Research UK (grant C6946/A24843). For the purpose of open access, the authors have applied a CC BY public copyright license to any author accepted manuscript version arising from this submission. G.M.-Z. was funded by a European Molecular Biology Organization (EMBO) long-term fellowship (ALTF907-2014) and Asociación Española Contra el Cáncer (POSTD18021MILL). K.T. was supported by a Sir Henry Wellcome Fellowship (grant RG94424). T.B. was supported by the European Research Council (ERC; StG 309952) and the Helmholtz Association.