Keeping DNA Replication in Check: A New Mechanism Linking CRL4-DCAF12 and MCMBP

Every time a cell divides, it must make an exact copy of its DNA. This process, called DNA replication, is tightly controlled to prevent errors that could lead to genome instability and disease. A key part of this process involves a group of proteins known as MCMs (minichromosome maintenance proteins), which form a complex that unwinds DNA and ensures that each segment is copied only once.

Previous work from the Sedlackova lab discovered that different pools of the MCM complexes – the parental (old) and nascent (newly made) forms – are generated and tightly balanced within cells (Sedlackova et al, Nature, 2020). Maintaining this balance is crucial for faithful genome duplication, but the molecular mechanism behind it remained elusive.

In a new study, researchers from the Institute of Biophysics and the Institute of Molecular Genetics of the Czech Academy of Sciences have identified CRL4-DCAF12 as a key player in this process. This protein complex acts as a regulator that fine-tunes the production of nascent MCM complexes, ensuring that DNA replication proceeds efficiently and accurately.

Anoop Kumar Yadav (PhD student in Sedlackova laboratory), Alikhan Abdirov (PhD student in Cermak laboratory), and their colleagues discovered the new quality control step in the assembly of nascent MCM protein forms. During MCM production, another protein called MCMBP helps to assemble and transport newly synthesized MCM subunits into the cell nucleus. Once there, CRL4-DCAF12 steps in to remove MCMBP through targeted degradation, allowing the final assembly of the full MCM2-7 complex. Without CRL4-DCAF12, this assembly is disrupted, leading to fewer functional MCMs on chromatin, accelerated replication forks, and ultimately, genome instability.

A model describing the production of nascent MCM2-7 helicases and its impact on genome duplication. Adapted from Yadav et al, Nature Communications, 2025.

This work uncovers a previously unknown layer of control of DNA replication preceding origin licensing and shows how protein degradation and assembly are coordinated to maintain genome integrity. By revealing how cells regulate nascent MCM production, the study provides important insights into the molecular basis of genome stability and how its failure can contribute to tumor development.

You can read the full article here.

This research was supported by the Czech Science Foundation (22-20303M), European Union (ERA grant agreement no. 101090292), the EMBO Installation Grant (IG-5689-2024), and funding from collaborating institutions.