New Insights into How DNA Nicks Could Be Key in Fighting Resistant BRCA Cancers

**Research conducted by Drs. Sharon Cantor and Jenna M. Whalen at UMass Chan Medical School has unraveled a novel mechanism through which cancer-fighting drugs target BRCA1 and BRCA2 tumor cells.** Published in *Nature Cancer*, their study shows how a small DNA nick—defined as a break in one strand of the DNA—can expand into a large single-stranded DNA gap, which effectively kills BRCA mutant cancer cells, including those resistant to existing therapies like PARP inhibitors. BRCA1 and BRCA2 are crucial tumor suppressor genes involved in DNA repair, and mutations in these genes significantly increase cancer risk. While traditional treatments cause DNA damage to trigger cell death, pinpointing the exact lethal cause has been challenging due to the varied damage caused by these drugs. The team employed **CRISPR technology** to introduce small DNA nicks in various breast cancer cell lines, including those deficient in BRCA1 or BRCA2. They discovered that cells deficient in these genes are particularly sensitive to nicks, more so than to double-strand breaks. This sensitivity arises because these nicks expand into long DNA gaps, a process distinct from the previously believed DNA double-strand break repair failure. Their findings highlight the excessive resection of nicks into gaps as the primary mechanism of cell lethality. Whalen and Cantor's research suggests that therapies existing today, like PARPi, may work by producing nicks, exploiting the inability of BRCA-deficient cells to manage these lesions effectively. For cancers that have developed resistance to PARPi, inducing nicks through alternative methods, like ionizing radiation, could provide a promising strategy to exploit these vulnerabilities, offering a path forward in treating resistant cancer cells.