Researchers at the Rockefeller University have clarified the mechanism by which certain types of breast cancer become immune to specific drugs designed to eliminate them. More specifically, they figured out how the loss of the protein 53BP1 due to BRCA1 mutation allows cancers to become insensitive to PARP inhibitors .
In DNA repair, the resection of double-strand breaks dictates the choice between homology-directed repair—which requires a 3′ overhang—and classical non-homologous end joining, which can join unresected ends1,2 . BRCA1-mutant cancers show minimal resection of double-strand breaks, which renders them deficient in homology-directed repair and sensitive to inhibitors of poly(ADPribose) polymerase 1 (PARP1)3–8 . When BRCA1 is absent, the resection of double-strand breaks is thought to be prevented by 53BP1, RIF1 and the REV7–SHLD1–SHLD2–SHLD3 (shieldin) complex, and loss of these factors diminishes sensitivity to PARP1 inhibitors4,6–9 . Here we address the mechanism by which 53BP1–RIF1–shieldin regulates the generation of recombinogenic 3′ overhangs. We report that CTC1–STN1–TEN1 (CST)10, a complex similar to replication protein A that functions as an accessory factor of polymerase-α (Polα)–primase11, is a downstream effector in the 53BP1 pathway. CST interacts with shieldin and localizes with Polα to sites of DNA damage in a 53BP1- and shieldin-dependent manner. As with loss of 53BP1, RIF1 or shieldin, the depletion of CST leads to increased resection. In BRCA1-deficient cells, CST blocks RAD51 loading and promotes the efficacy of PARP1 inhibitors. In addition, Polα inhibition diminishes the effect of PARP1 inhibitors. These data suggest that CST–Polα-mediated fill-in helps to control the repair of double-strand breaks by 53BP1, RIF1 and shieldin.
BRCA genes and cancer
BRCA1 and BRCA2 (breast cancer 1 and 2) are two of the tumor suppressor genes expressed in breast tissue; they encode for proteins that are used to repair damaged DNA. Mutations of these genes may damage them enough to impair DNA repair processes, thereby increasing cancer risk; indeed, bearers of BRCA1 mutations have an over 40% risk of developing the disease by age 80.
The proteins that these two genes encode for are used to repair so-called double-strand breaks—cuts along the double helix’s length. If these genes are lacking, so are the proteins used for DNA repair, resulting in faulty fixes that may be the prelude to cancer. However, in the case of BRCA1, its lack isn’t just a potential trigger of cancer; it is also its undoing, as scientists have exploited the defect and turned it against the disease.
A class of drugs known as PARP inhibitors is capable of inducing the very same kind of DNA damage that BRCA1-deficient cells are unable to repair. Targeting breast cancer cells in patients bearing the deficiency causes DNA damage that cannot be properly compensated for, ultimately leading to the demise of the tumor.
However, in cancer’s finest tradition, PARP inhibitors become ineffective in some cases; tumors that should be sensitive to the drugs are no longer such, because they have found a way around the inhibitors. While this may happen for more than one reason, Rockefeller University researchers have figured out how this happens in the specific case of cancer cells lacking a protein called 53BP1.
53BP1 and how it works
It has been known for a while that cells deprived of the 53BP1 protein are capable of repairing double-strand breaks even if they lack the BRCA1 gene. This means that BRCA1-defective cancerous cells are no longer affected by PARP inhibitors if they happen to mutate in such a way that the 53BP1 protein is lost; they will still have their DNA damaged by PARP inhibitors, but they will be able to repair it, thereby escaping death.
The original hypothesis as to 53BP1’s role in preventing DNA repair was that it prevented either string of the double strand from being trimmed back—an essential condition for repairing this kind of DNA damage. However, Rockefeller University researchers figured out that 53BP1 actually rewrites the very same sections that were cut off the DNA string right back where they used to be before the trimming took place. In turn, this leads to an imperfect repair and eventual cell death.
In normal circumstances, this is what happens in BRCA1-deficient cancer cells treated with PARP inhibitors; however, if some of them happen to lose 53BP1, administering inhibitors will just weed out 53BP1-equipped cancer cells, leaving the other, 53BP1-free ones free to thrive and eventually take over.
Armed with this knowledge, researchers might one day be able to devise tools to figure out which patients would be more responsive to PARP inhibitor therapy, and whether or not this should be accompanied by other drugs.
 Mirman Z., Lottersberger, F., Takai, H., Kibe, T., Gong, Y., Takai, K., Bianchi, A., Zimmermann, M., Durocher, D., & de Lange, T. (2018). 53BP1–RIF1–shieldin counteracts DSB resection through CST- and Polα-dependent fill-in, Nature.