A DNA break is very common and nothing to worry about. Cells are perfectly equipped with “repair technicians” that can fix these breaks, although some of them are sloppier than others. In people with BRCA1 gene mutations who are diagnosed with breast or ovarian cancer, the best repair technicians don’t work properly. This results in errors in the repaired DNA, which may lead to uninhibited cell division. Drugs called PARP inhibitors cleverly use this erroneous repair. They damage the tumor DNA which kills the tumor cells.
Not all patients with breast or ovarian cancer respond well to treatment with these inhibitors. That’s why Jacqueline Jacobs and her research group are investigating a certain DNA “shield”. In 2015, they discovered that the protein MAD2L2 plays an unexpectedly important role in DNA repair activities.
Three years later, Jacobs’ team discovered, in collaboration with several other labs, that this MAD2L2 has three allies. They named this the shieldin complex because it shields the ends of the DNA from strand breaks. This protection allows the fast but sloppy repairing agents to do their jobs. If one of these four proteins is missing, they cannot form a shield and the rapid repair technicians will not work. In cancer cells with a BRCA1 gene mutation, this also means that the “best repairers” can get back to work. These cells become desensitized to treatment with PARP inhibitors.
