Equilibrium between nascent and parental MCM proteins protects
Equilibrium between nascent and parental MCM proteins protects replicating genomes Journal Club 04/11/2020 Edison
Introduction The MCMs (Minichromosome Maintenance) proteins are DNA-dependent ATPases that bind to replication origins and license them to support a single round of DNA replication The CMG (CDC 45 -MCM-GINS) is the helicase required for genome duplication The formation of pre-RCs involves loading of nearly all MCM 2 -7 units onto chromatin in G 1 phase but only 510% of pre-RCs give rise to active replisomes
How MCM levels are maintened? The newly synthesized MCMs components cpmpensate for the gradual decay of preexistent MCMs
Which is the function of parental and nascent MCM inherited by daughter cells? Chromatin bound MCM 4 CDT 1: licensing factor MLN 4924: stabilize CDT 1 Daughter cells have a twofold excess of nascent MCMs but the parental MCMs are favoured to form active CMG helicase
How MCMs proteins sustain their steady-state levels and the inherited ratio between parental and nascent pools? Chromatin bound MCM 4 MCMBP should play a role in sustaining the influx of nascent MCM subunits to the entire pool of licensing-competent MCMs
How MCMBP regulates the MCMs subunits influx… Cytoplasmic MCM 4 Cytoplasmic MCM 2 Nuclear MCM 4 MCMBP facilitates nuclear import of nascent MCM 3 -7 subunits by conferring a strong NLS on the complex
…and stability? The physical interaction of MCMBP with MCM 3 -7 is critical for their nuclear transport and for shielding against unsheduled proteolysis
How MCMs influence replisome dynamics? Chromatin bound MCM 4 Impairment of pre-RC formation by partial depletion of CDC 6, or reducing the amount of pre-RCs composed of nascent MCMs by MCMBP degradation, accelerate forks and increase DNA damage response to a similar extent
Why replisome acceleration as a result of reduced pre-RC formation causes DNA damage? Increased incidence of fork asymmetry and increased speed of replication forks above the physiological limit
Conclusion • The MCM pool is sustained by continous recycling of once-licensed parental MCMs and simultaneous synthesis of nascent MCMs in mother cells, ensuring that daughter cells receive a sufficient amount of licensing-competent MCM units • The parental MCMs are more readly converted to active, replicative CMG helicases • MCMBP safeguards nascent MCM 3 -7 from unsheduled degradation and ensures MCM 3 -7 nuclear import • The MCMBP depletion brings to compromised MCM inheritance, reduced pre-RC formation, increased S-phase-specific DNA-damage response and generation of micronuclei in daughter cells • The high surplus of MCMs is vital to enforce the physiological speed of replication forks
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