CRL4^DCAF12regulation of MCMBP ensures optimal licensing of DNA replication

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 replication¹. However, the mechanism responsible for generating these pools and maintaining their equilibrium remains largely unexplored. Here, we identified CRL4^DCAF12as a new 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^2,3. Once in the nucleus, the MCM2 subunit must be incorporated into the MCM3-7 subcomplex, while MCMBP needs to be removed. CRL4^DCAF12facilitates the degradation of MCMBP and thereby regulates the assembly of MCM2-7 complexes. The absence of CRL4^DCAF12adversely affects the level of chromatin-bound nascent MCMs, resulting in accelerated replication forks and genome instability. Collectively, our findings uncovered the molecular mechanism underlying nascent MCM production essential to counteract genome instability and tumor formation.