Molecular Roadblock Prevents DNA-Damaged Cells from Dividing

Following the pathway is somewhat confusing for the uninitiated, as the initials assigned to the various proteins involved can read like so much alphabet soup.

The pathway, as described in the July 25, 2008, issue of the journal Cell, becomes activated when there is DNA damage in the G2 phase of the cell cycle and, mammalian cells must avoid entry into mitosis and instead initiate DNA repair. Initially, the phosphatase Cdc14B translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase APC/CCdh1, with the consequent degradation of Plk1, a prominent mitotic kinase. This process induces the stabilization of Claspin, an activator of the DNA-damage checkpoint, and Wee1, an inhibitor of cell-cycle progression, and allows an efficient G2 checkpoint. The G2 checkpoint is the roadblock that prevents the cell from dividing until the DNA repair is complete.

As a by-product of APC/CCdh1 reactivation in DNA-damaged G2 cells, Claspin is targeted for degradation. However, the deubiquitylating enzyme Usp28 counteracts this process to permit Claspin-mediated activation of Chk1 in response to DNA damage.

Since tumor cells already have a less efficient checkpoint because of defects in other regulatory pathways, inhibiting this newly described pathway with a drug could make cancer cells especially vulnerable to DNA damage, causing cancerous cells to die rather than pausing to repair the damage.

"One of the major messages of this study is that we have a new pathway that responds to DNA damage,” explained senior author Dr. Michele Pagano, professor of oncology and pathology at the New York University School of Medicine.


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New York University School of Medicine