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Regulated TRESLIN-MTBP loading governs initiation zones and replication timing in human DNA replication [ChIP-Seq]

ABSTRACT: Replication origins in human cells form clusters ranging from tens to hundreds of kilobases called initiation zones (IZs), typically located in intergenic regions between active genes. On a larger megabase scale, chromosomes replicate in a temporally defined replication timing (RT) pattern, where euchromatic regions replicate early, and heterochromatic regions replicate late. Although the stochastic model of IZ firing with a temporally regulated limiting factor can explain RT formation, this limiting factor in human cells remains unclear. To investigate the relationship between IZ and RT, we mapped the temporal firing pattern of IZs and examined the genome-wide distributions of replication licensing and firing factors in human cells. We identified TRESLIN-MTBP as the key limiting firing factor for replication initiation. Its loading onto phosphorylated MCM2–7 double hexamer (MCM-DH) is controlled by the opposing phosphorylation events on MCM-DH by Dbf4-dependent kinase and RIF1-Protein Phosphatase 1, which ultimately determine IZs and establish RT.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293195 | GEO | 2025/10/27

REPOSITORIES: GEO

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Regulated TRESLIN-MTBP loading governs initiation zones and replication timing in human DNA replication [RNA-Seq]

Project description:Replication origins in human cells form clusters ranging from tens to hundreds of kilobases called initiation zones (IZs), typically located in intergenic regions between active genes. On a larger megabase scale, chromosomes replicate in a temporally defined replication timing (RT) pattern, where euchromatic regions replicate early, and heterochromatic regions replicate late. Although the stochastic model of IZ firing with a temporally regulated limiting factor can explain RT formation, this limiting factor in human cells remains unclear. To investigate the relationship between IZ and RT, we mapped the temporal firing pattern of IZs and examined the genome-wide distributions of replication licensing and firing factors in human cells. We identified TRESLIN-MTBP as the key limiting firing factor for replication initiation. Its loading onto phosphorylated MCM2–7 double hexamer (MCM-DH) is controlled by the opposing phosphorylation events on MCM-DH by Dbf4-dependent kinase and RIF1-Protein Phosphatase 1, which ultimately determine IZs and establish RT.

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The Human Pre-replication Complex is an Open Complex

Project description:In eukaryotes, DNA replication initiation requires assembly and activation of the minichromosome maintenance (MCM) 2-7 double hexamer (DH) to melt origin DNA strands. However, the mechanism for this initial melting is unknown. Here, we report a 2.59-Å cryo-electron microscopy structure of the endogenously purified human MCM-DH (hMCM-DH), also known as the pre-replication complex. In this structure, the hMCM-DH shows a constricted central channel with a diameter of only 13 Å at the hexamer interface. This unusual conformation untwists and stretches the DNA strands such that almost a half turn of the bound duplex DNA is distorted with one-base pair completely separated, generating an initial open structure (IOS) at the hexamer junction. This IOS is captured and stabilized by zinc fingers (ZFs) of MCM2 and MCM5 from opposing hexamers. Disturbing the interaction between MCM5-ZF and the IOS demonstrably inhibits DH formation and replication initiation. High-resolution mapping of hMCM-DH footprints indicates that IOSs are distributed across the human genome in large clusters aligning perfectly with initiation zones to safeguard robust stochastic origin firing. This work unravels an intrinsic mechanism that couples DH formation with initial DNA melting to license replication initiation in human cells.

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