Novel role of BRCA1 in tumor suppression

Individuals with inherited mutations in BRCA1 are predisposed to breast, ovarian and other cancers. BRCA1 helps prevent cancer by repairing damaged DNA, but how it does so remains to be determined.

The damage in question is the DNA double-strand break, where both strands of DNA are broken and can lead to cancer if not repaired or if repaired inaccurately. The new research led by UT Health San Antonio shows that BRCA1 not only pushes a DNA break toward an accurate DNA repair mechanism called homologous recombination (HR) but also promotes subsequent steps by spurring the activity of “end resection enzymes” that process DNA ends to prepare them for HR.

“Our biochemical analysis with purified BRCA1 protein helps illuminate its role in DNA end processing,” said Patrick Sung, DPhil, associate dean for research at UT Health San Antonio and director of its Greehey Children’s Cancer Research Institute. He is a senior author of the new study titled, “Promotion of DNA end resection by BRCA1-BARD1 in homologous recombination,” published Sept. 11 in the journal Nature.

“This study helps us understand why BRCA1 is such an important tumor suppressor, as it really plays more than one critical role in HR,” said Sandeep Burma, PhD, 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.

Other authors also are with UT Health San Antonio, Mays Cancer Center, the Greehey Institute and the university’s Department of Biochemistry and Structural Biology, Department of Neurosurgery and Department of Medicine; University of Michigan; Columbia University Irving Medical Center; and University of Texas Southwestern Medical Center.

The study results come as October is Breast Cancer Awareness Month.

Explaining BRCA1 as a tumor suppressor

Burma said BRCA1 has been understood to prevent cancer by enforcing a decision-making step when the cell is faced with a DNA break — whether to repair using what’s called an “erroneous” mechanism (non-homologous end joining, NHEJ) or an “error-free” mechanism (homologous recombination, HR). BRCA1 acts to channel DNA breaks into HR for repair, Burma said.

The new study provides valuable mechanistic information on how BRCA1 achieves this impressive feat. The new findings explain the tumor suppressor function of BRCA1 through the promotion of key steps in error-free repair.

Sung said that this study is a team effort involving biochemists and cancer biologists at UT Health San Antonio and exemplifies the highly collaborative nature of research being carried out at the Mays Cancer Center.

The Sung laboratory is one of the few in the world with the capacity to purify large DNA repair proteins like BRCA1 and study them in the test tube. By generating finely crafted mutants of BRCA1 that are deficient in interaction with DNA but normal in all other aspects, they were able to pinpoint exactly how BRCA1 promotes error-free DNA repair.

Their findings were then confirmed at the cellular level by the Burma laboratory, which showed how cells expressing these mutants were unable to carry out error-free DNA repair. As a consequence, mutant cells exhibited gross chromosomal changes because of heightened levels of erroneous repair.

Burma said that UT Health San Antonio is poised to become a leader in the field of genome maintenance research as is evident from the award of a recent program project grant of $12.6 million from the National Cancer Institute to study DNA end resection and DNA break repair pathway choice. The program project, led by Sung, involves Burma as a project leader, and also Eric C. Greene, PhD, professor of biochemistry and molecular physics at Columbia University, another lead author of this study.

Greene’s laboratory has the unique ability to visualize the behavior of DNA repair proteins on a single DNA molecule in real time. They show in this study how BRCA1 travels with resection enzymes on DNA, spurring them on, much like how a jockey would spur a horse on the racetrack.

The findings have important implications for understanding how dysfunction in BRCA1 leads to oncogenesis, or the complex multi-step process by which normal cells become transformed to cause cancerous growth in the body. These findings will also help inform therapeutic options for breast and other cancers harboring specific mutations in BRCA1 affecting these novel functions of the protein.