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CRL4DCAF12 regulation of MCMBP ensures optimal licensing of DNA replication

Yadav, A. K.; Abdirov, A.; Ondruskova, K.; Negi, S.; Kolarova, K.; Dibus, N.; Krejci, J.; Polasek-Sedlackova, H.; Cermak, L.

2024-11-28 cell biology
10.1101/2024.11.26.625391 bioRxiv
Show abstract

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 CRL4DCAF12 as 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 nucleus2,3. 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 genome instability. Collectively, our findings uncovered the molecular mechanism underlying nascent MCM production essential to counteract genome instability and tumor formation.

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