A new mechanism for ensuring robust DNA replication

MCMBP promotes the assembly of the MCM2–7 hetero-hexamer to ensure robust DNA replication in human cells

Yuichiro Saito, Venny Santosa, Kei-ichiro Ishiguro and Masato T. Kanemaki.

eLife (2022) 11, e77393 DOI:10.7554/eLife.77393

Replication of the genetic material DNA is essential for cell proliferation. The MCM2–7 hexamer, a ring-like complex composed of six subunits from MCM2 to MCM7, functions as the replicative helicase for unwinding double-stranded DNA. It is known that a large amount of the MCM2–7 hexamer is required for efficient DNA replication in the S phase. However, how the MCM2–7 hexamer is assembled has not been understood.

This paper shows that the MCM-binding protein (MCMBP) binds to the MCM subunits and plays a crucial function in incorporating MCM3 and MCM5 into the hexamer (Figure 1). Rapid degradation of MCMBP using the auxin-inducible degron 2 system (AID2) resulted in a reduced expression of the functional MCM2–7 hexamer at each cell division because newly synthesized MCM3 was not incorporated into the hexamer.


Figure1: A model showing how MCMBP promotes the assembly of the MCM2–7 hexamer. In cells depleted of MCMBP, MCM3 and MCM5 are not incorporated into the hexamer causing degradation of these two proteins.

Interestingly, when the level of MCM2–7 hexamer decreased, human cells expressing the tumor suppressor gene p53 maintained genome integrity by transiently arresting the cell cycle in the G1 phase (Fig. 2). In contrast, cells lacking p53 induced cell death by entering the S phase with fewer hexamers resulting in incomplete DNA replication. These results suggest that depletion of MCMBP may specifically eliminate cancer cells with mutations in p53.


Figure2: The absence of the tumor suppressor gene, p53, affects the fate of cells depleted of MCMBP. The genomic DNA become unstable causing cell death in cells without p53.

The Kanemaki Laboratory at National Institute of Genetics led this research in collaboration with Prof. Kei-ichiro Ishiguro at Kumamoto University.

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