A new study led by The University of Texas Health Science Center at San Antonio (UT Health San Antonio) has uncovered a novel role of the breast cancer gene 1 (BRCA1) in tumor suppression. Individuals with inherited mutations in BRCA1 are at a higher risk for developing breast, ovarian, and other cancers. BRCA1 helps prevent cancer by repairing damaged DNA, specifically double-strand breaks that, if left unrepaired or inaccurately repaired, can lead to cancer. The research conducted by UT Health San Antonio shows that BRCA1 not only aids in pushing DNA breaks towards accurate repair through homologous recombination (HR), but also promotes subsequent steps by enhancing the activity of end resection enzymes that process DNA ends for HR.
The senior authors of the study, Patrick Sung and Sandeep Burma from UT Health San Antonio, highlighted the critical role of BRCA1 in HR and tumor suppression. BRCA1 is vital in preventing cancer by directing DNA breaks towards error-free repair as opposed to erroneous repair mechanisms such as non-homologous end joining (NHEJ). The new study provides valuable mechanistic insights into how BRCA1 accomplishes this function by promoting key steps in error-free repair. The collaborative effort involving biochemists and cancer biologists at UT Health San Antonio exemplifies the highly collaborative nature of research being carried out at the Mays Cancer Center.
The study utilized sophisticated techniques to purify large DNA repair proteins like BRCA1 and study their interactions in the test tube. By creating precise mutants of BRCA1 that lacked DNA interaction ability but maintained normal function in other aspects, researchers were able to determine how BRCA1 promotes error-free DNA repair. Cellular experiments conducted by the Burma laboratory confirmed that cells expressing these mutants were unable to carry out error-free DNA repair, leading to chromosomal changes due to increased levels of erroneous repair. This research indicates that UT Health San Antonio is becoming a leader in genome maintenance research, as evidenced by a recent $12.6 million program project grant from the National Cancer Institute to study DNA end resection and DNA break repair pathway choice.
The study also involved research collaboration with Eric C. Greene from Columbia University, who is a lead author of the study. Greene’s laboratory has unique capabilities to visualize the behavior of DNA repair proteins on a single DNA molecule in real-time. They demonstrated how BRCA1 works with resection enzymes on DNA, stimulating their activity, similar to how a jockey spurs a horse on a racetrack. These findings have significant implications for understanding how dysfunction in BRCA1 contributes to oncogenesis, the process by which normal cells transform into cancerous cells. This research will also aid in developing therapeutic options for breast and other cancers with mutations in BRCA1 that affect these novel functions of the protein. The results of the study coincide with Breast Cancer Awareness Month in October.
