DNA repair with a hefty price tag

Barton et al. identify a last-ditch repair mechanism that enables cells to enter S phase without DNA breaks.

Nonhomologous end joining (NHEJ) repairs DNA double-strand breaks throughout the cell cycle. In contrast, homologous recombination (HR) handles only breaks that occur during G2 or S phase. The enzyme CtIP triggers HR by stripping away the bases from one DNA strand to create a sticky overhang, a maneuver known as resection. CtIP also takes part in NHEJ during G1, although how the enzyme is activated during this phase of the cell cycle is unknown.

Barton et al. discovered that polo-like kinase 3 (Plk3) does the job. DNA damage during G1 spurs Plk3 to activate CtIP and stimulate resection. Cells that can’t readily repair breaks by traditional NHEJ, which doesn’t involve resection, can still restore their DNA during G1, the researchers determined. They use a mechanism involving Plk3 and CtIP that is a variant form of NHEJ. The process is necessary for healing complex breaks in which several DNA injuries are close to one other. Barton et al. found that depleting Plk3 or CtIP hampered repair of these breaks.

But there’s a downside to DNA repair that relies on Plk3 and CtIP. It can induce translocations and genomic rearrangements, presumably because the sticky overhangs created by resection tangle with other DNA molecules. Despite the risk, cells might turn to this mechanism when they are pressed for time and are trying to avoid entering S phase with broken DNA. The study reveals that Plk3 initiates repair of damage caused by certain kinds of radiation, suggesting that inhibiting the kinase might increase the vulnerability of tumors to radiation treatment.