The dynamic equilibrium of nascent and parental MCMs safeguards replicating genomes

The MCM2-7 (minichromosome maintenance) protein complex is a DNA unwinding motor required for the eukaryotic genome duplication 1 . Although a huge excess of MCM2-7 is loaded onto chromatin in G1 phase to form pre-replication complexes (pre-RCs), only 5-10 percent are converted into a productive CDC45-MCM-GINS (CMG) helicase in S phase – a perplexing phenomenon often referred to as the ‘MCM paradox’ 2 . Remaining pre-RCs stay dormant but can be activated under replication stress (RS) 3 . Remarkably, even a mild reduction in MCM pool results in genome instability 4, 5 , underscoring the critical requirement for high-level MCM maintenance to safeguard genome integrity across generations of dividing cells. How this is achieved remains unknown. Here, we show that for daughter cells to sustain error-free DNA replication, their mothers build up a stable nuclear pool of MCMs both by recycling of chromatin-bound MCMs (referred to as parental pool) and synthesizing new MCMs (referred to as nascent pool). We find that MCMBP, a distant MCM paralog 6 , ensures the influx of nascent MCMs to the declining recycled pool, and thereby sustains critical levels of MCMs. MCMBP promotes nuclear translocation of nascent MCM3-7 (but not MCM2), which averts accelerated MCM proteolysis in the cytoplasm, and thereby fosters assembly of licensing-competent nascent MCM2-7 units. Consequently, lack of MCMBP leads to reduction of nascent MCM3-7 subunits in mother cells, which translates to poor MCM inheritance and grossly reduced pre-RCs formation in daughter cells. Unexpectedly, whereas the pre-RC paucity caused by MCMBP deficiency does not alter the overall bulk DNA synthesis, it escalates the speed and asymmetry of individual replisomes. This in turn increases endogenous replication stress and renders cells hypersensitive to replication perturbations. Thus, we propose that surplus of MCMs is required to safeguard replicating genomes by modulating physiological dynamics of fork progression through chromatin marked by licensed but inactive MCM2-7 complexes.