New DNA Repair Mechanism in Tuberculosis Uncovered
Tuberculosis (TB) remains a significant threat to much of the world’s population—affecting up to two billion people annually. It has sat, unwavering, near the top of the list for deadliest diseases. Moreover, current therapeutics to treat the disease are becoming increasingly ineffective as drug resistance continues to rise exponentially. Now, new research from investigators at the University of Sussex and the Polish Academy of Sciences has identified two key proteins that allow Mycobacterium tuberculosis, the causative agent of TB, to remain undetected within cells designed to destroy them. Findings from the new study were published today in Nature Communications in an article entitled “DNA Ligase C and Prim-PolC Participate in Base Excision Repair in Mycobacteria.”
“Mycobacteria are incredibly resilient and can remain dormant for many years inside cells, where they are exposed to significant levels of free radical damage designed to kill foreign invaders,” explained senior study investigator Aidan Doherty, Ph.D., professor of biochemistry at the University of Sussex. “However, these bacteria survive using complex repair mechanisms that protect their genomes from these attacks.”
More than 10.6 million people worldwide fell ill and 1.7 million died from tuberculosis last year, while a quarter of the world has latent TB, which will develop into active tuberculosis for one in ten of the victims, years or even decades later. TB is notoriously difficult to treat, with current drug treatments often producing debilitating side effects within patients, including muscle wastage and loss of sight.
In previous research, the University of Sussex team discovered that mycobacteria repair DNA breaks using an enzyme complex called ligase D (LigD). The latest study establishes that a closely related protein apparatus called ligase C, whose function was unclear until now, combines with other repair proteins to fix damaged DNA bases in mycobacterial genomes caused by the attack of oxygen free radicals.
“…we show that the LigC complex interacts with core BER [base excision repair] enzymes in vivo and demonstrate that together these factors constitute an excision repair apparatus capable of repairing damaged bases and abasic sites,” the authors wrote. “The polymerase component, which contains a conserved C-terminal structural loop, preferentially binds to and fills-in short gapped DNA intermediates with RNA and LigC ligates the resulting nicks to complete repair. Components of the LigC complex, like LigD, are expressed upon entry into stationary phase and cells lacking either of these pathways exhibit increased sensitivity to oxidizing genotoxins.”
Interestingly, deleting LigC reduced mycobacteria’s ability to repair and survive oxidative DNA damage. Deleting both LigC and LigD lowered their survival rate even further, suggesting that inhibiting these repair mechanisms could be exploited to develop novel antimicrobial strategies.
“We have shown that by removing LigC and LigD, mycobacterial cells become much more sensitive to oxidative damage,” Dr. Doherty concluded. “With further investigation of these protective mechanisms, it is hoped that this research will pave the way for the development of new drugs to more successfully target mycobacteria.”