Highly Conserved DNA Repair Proteins Have Role in Cancer Predisposition

During evolution and development of a species, the replication of the organism’s genome can lead to a duplication of certain genes that evolve new functions. These so-called paralogs are found throughout the genome of humans, as well as other organisms, and are associated with a variety of cellular processes. Yet, the paralogs that are involved with the homologous recombination repair of damaged DNA have been studied intently for many years with the hope of better understanding the mechanisms used to maintain genomic integrity.

Now, researchers from the University of Pittsburgh, School of Medicine have uncovered the mechanism by which conserved paralog proteins repair DNA damage and how their malfunction could lead to the development of tumors. Specifically, the researchers examined the interactions of the DNA repair protein paralogs of RAD51, which has been shown previously to have a strong association with breast and ovarian tumors.  

“These are proteins that have been present throughout evolution in many species, but very little has been known about what they do,” explained senior investigator Kara Bernstein, Ph.D., assistant professor of microbiology and molecular genetics at Pitt School of Medicine. “Our study shows for the first time the mechanism of how they are involved in the repair of damaged DNA.”

The findings from this study were published recently in Nature Communications through an article entitled “Promotion of presynaptic filament assembly by the ensemble of S. cerevisiae Rad51 paralogues with Rad52.”

The Pitt investigators employed a classic molecular biology technique called yeast two-hybrid screening, which allows scientists to observe and discover protein-protein and protein-DNA interactions. The results from their analysis showed that two RAD51 paralogs interacted with two proteins of the Shu complex, which is involved in repairing DNA strand breaks—often caused by environmental chemicals, radiation, and other metabolic functions.

Additionally the researchers found that the Shu complex works synergistically with additional RAD51 paralogues in order to search for homologous DNA regions with double-strand breaks, in which opposite ends of the twisting DNA ladder have been broken. The RAD51 proteins and Shu complex repair the damage by filling in the missing pieces in a process called homologous recombination repair.

Dr. Bernstein and her colleagues were excited by their findings and feel that from their results they can begin to postulate a function for the human RAD51 paralogs having a role in the mechanisms that cells employ in order to avoid cancerous phenotypes.

“Now that we understand what the proteins do, we can perhaps tailor therapies for patients who have cancer and mutations in these repair genes,” Dr. Bernstein concluded.