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Human ORC/MCM density is low in active genes and correlates with replication time but does not solely define replication initiation zones

By Nina Kirstein, Alexander Buschle, Xia Wu, Stefan Krebs, Helmut Blum, Wolfgang Hammerschmidt, Laurent Lacroix, Olivier Hyrien, Benjamin Audit, Aloys Schepers

Posted 15 Aug 2020
bioRxiv DOI: 10.1101/2020.08.15.252221

Eukaryotic DNA replication initiates during S phase from origins that have been licensed in the preceding G1 phase. Here, we compare ChIP-seq profiles of the licensing factors Orc2, Orc3, Mcm3, and Mcm7 with gene expression, replication timing and fork directionality profiles obtained by RNA-seq, Repli-seq and OK-seq. ORC and MCM are strongly and homogeneously depleted from transcribed genes, enriched at gene promoters, and more abundant in early- than in late-replicating domains. Surprisingly, after controlling these variables, no difference in ORC/MCM density is detected between initiation zones, termination zones, unidirectionally replicating and randomly replicating regions. Therefore, ORC/MCM density correlates with replication timing but does not solely regulate the probability of replication initiation. Interestingly, H4K20me3, a histone modification proposed to facilitate late origin licensing, was enriched in late replicating initiation zones and gene deserts of stochastic replication fork direction. We discuss potential mechanisms that specify when and where replication initiates in human cells. ### Competing Interest Statement The authors have declared no competing interest.

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