Ambra Dondi

The DNA damage checkpoint is a surveillance mechanism evolved to preserve genome integrity in response to DNA damaging agents. The DNA damage checkpoint senses DNA insults and halts the cell cycle providing time and conditions to repair the lesion(s). If the damage is successfully repaired, cells reenter in the cell cycle in a process known as checkpoint recovery. If the damage is not repaired, cells either die or override the checkpoint reentering the cell cycle in the presence of the lesion. This process, known as checkpoint adaptation, represents an opportunity for cells to repair the damage in the following cell cycle. However, checkpoint adaptation can be an unsafe event as daughter cells can accumulate genomic aberrations. Indeed, checkpoint adaptation has been described to occur also in cancer cells.

The players involved in the adaptation process remains largely unknown. In budding yeast S. cerevisiae, it was shown that the activity of the Cdc fourteen early anaphase release (FEAR) network, a pathway that control the exit from mitosis, is required for checkpoint adaptation, therefore suggesting a crosstalk between the cell cycle machinery and the DNA damage checkpoint.

We found that the activity of single FEAR components is dispensable both in unperturbed conditions and following repair of the DNA lesion (i.e. checkpoint recovery). However, the activity of single FEAR components is strictly required for exit from mitosis in persistent DNA damage conditions, therefore suggesting checkpoint adaptation as the rewiring of a cell cycle with peculiar features.