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<p>The minichromosome maintenance (MCM2-7) protein complexes are central drivers of genome duplication. Distinct protein pools, parental and nascent MCMs, and their precise equilibrium are essential to sustain error-free DNA replication. However, the mechanism responsible for generating these pools and maintaining their equilibrium remains largely unexplored. Here, we identified CRL4<sup>DCAF12</sup> as a factor controlling the assembly of nascent MCM complexes. During MCM biogenesis, MCMBP facilitates the assembly and transport of newly synthesized MCM3-7 subcomplexes into the nucleus. Once in the nucleus, the MCM2 subunit must be incorporated into the MCM3-7 subcomplex, while MCMBP needs to be removed. CRL4<sup>DCAF12</sup> facilitates the degradation of MCMBP and thereby regulates the assembly of MCM2-7 complexes. The absence of CRL4<sup>DCAF12</sup> adversely affects the level of chromatin-bound nascent MCMs, resulting in accelerated replication forks and replication stress. Collectively, our findings uncovered the molecular mechanism underlying nascent MCM production essential to counteract genome instability.</p>

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CRL4DCAF12 regulation of MCMBP ensures optimal licensing of DNA replication

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Anoop Kumar Yadav,
  • Alikhan Abdirov,
  • Katarina Ondruskova,
  • Simran Negi,
  • Kristina Jamrichova,
  • Karolina Kolarova,
  • Nikol Dibus,
  • Jana Krejci,
  • Hana Polasek-Sedlackova,
  • Lukas Cermak

摘要

The minichromosome maintenance (MCM2-7) protein complexes are central drivers of genome duplication. Distinct protein pools, parental and nascent MCMs, and their precise equilibrium are essential to sustain error-free DNA replication. However, the mechanism responsible for generating these pools and maintaining their equilibrium remains largely unexplored. Here, we identified CRL4DCAF12 as a factor controlling the assembly of nascent MCM complexes. During MCM biogenesis, MCMBP facilitates the assembly and transport of newly synthesized MCM3-7 subcomplexes into the nucleus. Once in the nucleus, the MCM2 subunit must be incorporated into the MCM3-7 subcomplex, while MCMBP needs to be removed. CRL4DCAF12 facilitates the degradation of MCMBP and thereby regulates the assembly of MCM2-7 complexes. The absence of CRL4DCAF12 adversely affects the level of chromatin-bound nascent MCMs, resulting in accelerated replication forks and replication stress. Collectively, our findings uncovered the molecular mechanism underlying nascent MCM production essential to counteract genome instability.