Research indicates that the breast cancer gene 1 (BRCA1) not only ensures precise DNA repair to protect against cancer but also enhances tumor suppression activities afterward.
A recent investigation conducted by The University of Texas Health Science Center at San Antonio (UT Health San Antonio) reveals a new function of the breast cancer gene 1 (BRCA1) in tumor suppression.
People with inherited BRCA1 mutations face a higher risk of breast, ovarian, and other types of cancer. BRCA1 contributes to cancer prevention by repairing damaged DNA, though the exact mechanisms behind this process are still not fully understood.
The damage referenced involves a DNA double-strand break, a situation where both DNA strands are severed, potentially leading to cancer if the break isn’t repaired or if the repair is incorrect. The latest research from UT Health San Antonio demonstrates that BRCA1 not only directs DNA breaks toward an accurate repair method, known as homologous recombination (HR), but also enhances the following stages by activating “end resection enzymes” that prepare DNA ends for HR.
“Our biochemical analysis using purified BRCA1 protein sheds light on its role in processing DNA ends,” stated Patrick Sung, DPhil, associate dean for research at UT Health San Antonio and head of its Greehey Children’s Cancer Research Institute. He is a senior author of the study titled, “Promotion of DNA end resection by BRCA1-BARD1 in homologous recombination,” published on September 11 in the journal Nature.
“This research enhances our understanding of why BRCA1 is a crucial tumor suppressor, as it truly performs multiple essential roles in HR,” noted Sandeep Burma, PhD, a professor and vice chair (research) of neurosurgery at UT Health San Antonio and its Mays Cancer Center. He is a senior and co-communicating author of the study.
Additional contributors include researchers from UT Health San Antonio’s Mays Cancer Center, the Greehey Institute, and various departments, as well as collaborators from the University of Michigan, Columbia University Irving Medical Center, and University of Texas Southwestern Medical Center.
The study’s findings are particularly timely as October marks Breast Cancer Awareness Month.
Understanding BRCA1 as a tumor suppressor
Burma explained that BRCA1 has been recognized for its role in preventing cancer by facilitating a decision-making process when cells encounter DNA breaks, deciding whether to repair it using a faulty method (non-homologous end joining, NHEJ) or a reliable one (homologous recombination, HR). According to Burma, BRCA1 steers DNA breaks toward HR for accurate repair.
This new research offers crucial insights into how BRCA1 effectively accomplishes this vital function. It elaborates on the tumor suppressor characteristics of BRCA1 by promoting important steps in error-free repair.
Sung emphasized that this study reflects a collaborative effort among biochemists and cancer biologists at UT Health San Antonio, showcasing the teamwork involved in the investigations being conducted at the Mays Cancer Center.
The Sung laboratory is distinctly capable of purifying large DNA repair proteins like BRCA1 for in-depth study. By creating carefully designed BRCA1 mutants, which could not interact with DNA yet were otherwise normal, researchers were able to determine how BRCA1 encourages error-free DNA repair.
The results were validated at the cellular level by the Burma laboratory, which demonstrated that cells with these mutants could not perform error-free DNA repair. Consequently, these mutant cells showed significant chromosomal abnormalities due to increased mistaken repairs.
Burma mentioned that UT Health San Antonio is on track to become a pioneer in genome maintenance research, highlighted by a significant program project grant of $12.6 million from the National Cancer Institute, aimed at investigating DNA end resection and the decision-making pathways for DNA break repair. This project, led by Sung, includes Burma as a project leader, along with Eric C. Greene, PhD, a professor of biochemistry and molecular physics at Columbia University, who is also a lead author of this study.
Greene’s laboratory possesses a unique ability to visualize DNA repair proteins’ activities on a single DNA molecule in real-time. This study illustrates how BRCA1 moves alongside resection enzymes on DNA, motivating them much like a jockey urging a horse at the racetrack.
The implications of these findings are significant for understanding how BRCA1 malfunctions can lead to oncogenesis, the intricate process that transforms normal cells into cancerous growths. Furthermore, this research will aid in developing therapeutic strategies for breast and other cancers with specific BRCA1 mutations affecting its novel functions.
