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.

Department of Experimental Biology Faculty of Science Masaryk University Brno Czechia

Faculty of Science Charles University Prague Czechia

Institute of Biophysics Czech Academy of Sciences Brno Czechia

Laboratory of Cancer Biology Institute of Molecular Genetics Czech Academy of Sciences Prague Czechia

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