DNA damage and repair



Deoxyribonucleic acid or DNA contains the genetic instructions that determine the development and function of all living organisms. DNA is constantly under attack from various sources that cause damage to its structure. These sources include reactive oxygen species generated during normal metabolism, ultraviolet and ionizing radiation from the environment, and endogenous metabolic byproducts. Left unrepaired, the resulting DNA lesions and breaks can lead to mutations, genomic instability and ultimately cancer or cell death. As such, cells have evolved multiple DNA repair pathways that work concertedly to detect and repair different types of DNA damage, thus maintaining genomic integrity.



Base excision repair and its therapeutic potential



One of the main pathways for repairing basic DNA Repair Drugs damages like modified or mismatched bases is the base excision repair (BER) pathway. BER is a short-patch repair mechanism initiated by DNA glycosylases that recognize and remove damaged or inappropriate bases. The resulting abasic site is then cleaved by an apurinic/apyrimidinic endonuclease, after which DNA polymerase and ligase carry out repair synthesis and nick sealing. Defects in BER are associated with age-related disorders as well as increased cancer risk. Small molecule inhibitors of BER proteins like polymerase β or apurinic/apyrimidinic endonuclease 1 have shown promise in sensitizing cancer cells to chemotherapy without significant toxicity to normal cells. Further development of such targeted BER inhibitors could lead to effective anticancer therapies with reduced side effects.



Targeting PARP enzymes in BRCA-deficient cancers



The base excision repair pathway intersects with another important repair system called homologous recombination repair (HRR) in the later repair synthesis and ligation steps. HRR uses undamaged DNA as a template to accurately repair DNA double-strand breaks. Poly (ADP-ribose) polymerase or PARP enzymes are involved in early detection and signaling of DNA single-strand breaks that are later converted to double-strand breaks and channeled to HRR for repair. Cancer cells deficient in BRCA1/2 or other HRR proteins show “synthetic lethality” when PARP is also inhibited, leading to the accumulation of toxic unrepaired DNA damage and cell death. Several PARP inhibitors have been approved to treat BRCA-mutated breast, ovarian and prostate cancers. As PARP inhibitors continue to show efficacy and safety as maintenance therapies, their application might be broadened to other tumor types.



Photodynamic therapy and the promise of photosensitizers



Another strategy for cancer treatment involves the use of photodynamic therapy where non-toxic photosensitizing chemical agents are activated by visible light irradiation. This triggers the generation of cytotoxic reactive oxygen species like singlet oxygen that cause localized oxidative damage to membranes, proteins and nucleic acids including DNA in targeted cancer cells. Preferential accumulation of photosensitizers in tumor tissue allows selective destruction with minimal effects on surrounding healthy cells. Current research aims to design new targeted photosensitizers for improved tumor specificity and enhanced phototoxicity upon illumination. When combined with DNA repair inhibition, photodynamic therapy could achieve greater anticancer effects through increased and sustained DNA damage.



Targeted delivery of DNA repair blocking nanoparticles



Systemic delivery of DNA repair drugs inhibitors to target tissues remains a challenge. Nanomedicine-based approaches aim to address this issue by encapsulating therapeutic molecules within biocompatible nanoparticles for controlled and site-specific release. For instance, liposomes functionalized with tumor-targeting ligands have shown the capacity to ferry PARP inhibitors preferentially to tumors. Gold nanoparticles conjugated to BER inhibitors have been developed to light-activate DNA damage upon near-infrared irradiation of breast cancer cells. Researchers are also exploring the utility of exosome-mimicking nanoparticles to ferret DNA repair blockers selectively into cancer cells based on surface protein markers. Such targeted nanodelivery strategies could revolutionize the treatment of recalcitrant cancers in the future.



DNA repair modulation as an anti-aging therapy



In addition to cancer, declining DNA repair potential has been implicated in cellular senescence and aging. Studies suggest upregulating certain repair pathways could counteract age-related tissue degeneration and extend healthspan. For example, periodic calorie restriction is known to induce DNA repair gene expression through hormesis and may explain its anti-aging effects. Drugs that mimic this stress response and boost DNA repair capacity are being investigated. PARP inhibitors show promise for treating age-related conditions like progeria by attenuating the cellular senescence program. Mitochondria-targeted antioxidants help repair mitochondrial DNA damage accumulation with age. Modulating DNA repair through pharmacological or lifestyle interventions offers hope for delaying multiple aging diseases in the future.





Targeted inhibition of DNA repair drugs pathways is emerging as an effective cancer treatment strategy. Continued research into developing novel repair-blocking agents, optimizing their delivery using nanomedicine and combining them with DNA-damaging cancer therapies promises to revolutionize precision oncology. Beyond cancer, strategic DNA repair modulation also holds potential for treating devastating aging diseases and extending healthy longevity. With better mechanistic understanding and ongoing clinical evaluation, DNA repair-based therapies are positioned at the cutting edge of developing next-generation medicines against some of the most intractable diseases today.



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