HRR Pathway: The Custodian of Human DNA

by Taeeon Kong ’22

Subway stations and bus stops become quite messy after a busy day, and maintenance workers constantly work to keep them clean. Similarly, human DNA is frequently damaged by a myriad of internal and external factors, and such DNA damages are commonly referred to as “genetic mutations.” Groups of proteins work together in biological pathways to repair such damages, and some major pathways include homologous recombination repair, mismatch repair, and non-homologous end-joining. 

A pathway of particular interest in recent research has been homologous recombination repair (HHR) due to its close association with breast cancer, one of the most prevalent types of cancer in the United States. To understand the reasons behind the linkage, however, one must first examine the role and mechanisms of the HRR pathway. 

Homologous recombination is used to repair a specific type of genetic damage called double-strand breaks (DBSs), which results from UV radiation, genotoxic chemicals, erroneous DNA replication. In DBSs, significant genetic information could be permanently lost with an unreliable repair, because a portion from both strands of DNA are missing. This is why HRR uses an identical chromosome as spare parts to repair the faulty chromosome. 

More specifically, the HRR pathway initiates when the Mre11-Rad50-Nbs1 (MRN) protein complex locates the DSB, and consequently recruit a protein kinase called Ataxia Telangiectasia Mutated to power the pathway through phosphorylation. Once other necessary proteins are gathered at the breakage, MRN and a sensor protein called CtIP resects the nucleotides at the two ends of the breakage to essentially “clean up” the site. Immediately following the resection, replicative protein A (RPA) binds to both ends of the single-strand DNA (ssDNA) tails to protect them. Consequently, BRCA1/2 proteins replace RPA with Rad51, a nucleoprotein necessary for homology search. Once Rad51 binds to the ssDNA tail, it stretches and searches in an intact chromosome to find the sequence of nucleotides that are missing in the damaged chromosome. Once it is found, Rad51 assists in forming a physical connection between the two nucleotides, which results in a structure called displacement loop (D-loop). Once the D-loop intermediate is resolved, the repair is complete.

The HRR is a complex repair pathway involving many different proteins. Each protein plays a specific role in the process, and if some major ones are dysfunctional, the entire pathway may be compromised. BRCA1/2 are such major proteins. As previously explained, they play a critical role in allowing Rad51 to bind to the ssDNA, and thus, genetic mutations in BRCA1/2 disable the pathway. This condition is called homologous recombination repair deficiency (HRD), and it means that the cells are unable to repair its damaged DNA. This often leads to toxic accumulation of genetic variants and consequently causes carcinogenesis. 

The research on HRR and its mechanisms allows for immense developments in cancer treatment. Rebecca Arend, a professor of gynecologic oncology at the University of Alabama-Birmingham explains: “it used to be that all women with ovarian cancer got exactly the same therapy, and that’s not the case anymore.” Now, physicians can choose different courses of treatment that would be most effective for patients. Using the fact that cancer cells with HRD are vulnerable to double-strand breaks, physicians disclosed that treatment with PARP inhibitors may be effective for some cases of breast and ovarian cancer. “PARP inhibitors play a role to selectively disrupt DNA repair in cells with absent or dysfunctional BRCA genes” explains Craig Underhill, a researcher at the Insitut Bergonié Cancer Center. By undermining the cancer cells’ other means of DNA repair, physicians can selectively eliminate tumor cells. 

Evidently, continuing to research and understand the unexplored aspects of cellular mechanisms is crucial for medical developments in the future. Many researchers are continuously studying and analyzing data to provide crucial insights that could facilitate cancer treatment, and the BRCA exchange and the COSMIC database one of them. The BRCA Exchange aims to create a database of BRCA1/2 variants, which will allow physicians to easily look up specific genetic variants to check for pathogenicity. The COSMIC database organizes genetic variants into groups called “mutational signatures” which facilitate the diagnosis and identification of mutational processes. 

Many researchers transcended not only institutional, but also continental boundaries to work together on a common goal: to cure cancer. Though finding a “cure to cancer” is often seen as something unachievable, the continued efforts of thousands of researchers give hope to the cancer patients around the world, and eventually, the day will come when patients no longer tremble at the news of cancer.