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Stopping replication, at the beginning

Nature Chemical Biology volume 4, pages 331–332 (2008)Cite this article

A new pharmacological inhibitor of the Cdc7 protein kinase can block replication initiation without activating the replication checkpoint, thus validating replication initiation as a new target class for cancer cell chemotherapy.

With the current frenzy for molecularly targeted chemotherapy, it's hard to imagine that the earliest cancer therapies used nitrogen mustards and folic acid analogs. These agents achieved their efficacy by alkylative damage of DNA or by inhibiting the synthesis of nucleotide precursors. How do these DNA damaging agents kill cancer cells? It is now understood that blocking DNA synthesis at the level of DNA polymerase activity in turn blocks replication, which leads to activation of a “replication checkpoint” that stops damaged cells from proceeding into mitosis. These early therapies worked in part because checkpoints in noncancerous cells block damaged cells from cell division while their DNA is repaired, whereas cancer cells recklessly continue to divide, heading for further damage and death. In a new twist on chemotherapy, Montagnoli et al. have mounted an attack on cancer cells by targeting the earliest steps initiating DNA replication. They have developed a new inhibitor of the protein kinase Cdc7, a central regulator of replication initiation, and show that this inhibitor selectively inhibits an early step in replication, well upstream of DNA polymerase1. What may be even more surprising to some is that blocking replication initiation not only causes a failure in DNA replication but also bypasses the critical DNA damage checkpoint, leaving the door open for the cell to undergo further damage and eventual death.

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Figure 1: Cdc7 regulation of DNA replication and checkpoints in normal and tumor cells.

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  1. Department of Cell Regulation, Department of Pathology, Peter K. Jackson is at Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA and Stanford University School of Medicine, 300 Pasteur Drive, Palo Alto, California 94305, USA. pjackson@gene.com,

    Peter K Jackson

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  1. Peter K Jackson
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Jackson, P. Stopping replication, at the beginning. Nat Chem Biol 4, 331–332 (2008). https://doi.org/10.1038/nchembio0608-331

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  • DOI: https://doi.org/10.1038/nchembio0608-331

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