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<p>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 following temporally defined replication timing (RT), 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 map the temporal firing pattern of IZs and examine the genome-wide distributions of replication licensing and firing factors in human cells. We identify TRESLIN-MTBP as a 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.</p>

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Regulated TRESLIN-MTBP loading governs initiation zones and replication timing in human DNA replication

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月2日

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  • Xiaoxuan Zhu,
  • Atabek Bektash,
  • Yuki Hatoyama,
  • Sachiko Muramatsu,
  • Shin-Ya Isobe,
  • Chikashi Obuse,
  • Atsushi Toyoda,
  • Yasukazu Daigaku,
  • Chun-Long Chen,
  • Masato T. Kanemaki

摘要

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 following temporally defined replication timing (RT), 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 map the temporal firing pattern of IZs and examine the genome-wide distributions of replication licensing and firing factors in human cells. We identify TRESLIN-MTBP as a 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.