Introduction
Deoxyribonucleic acid (DNA) is the cornerstone of genetic information in every organism, ensuring the proper functioning and survival of cellular processes. However, DNA is not immune to damage. It is constantly subjected to harm from both internal and external sources, ranging from oxidative stress and telomere shortening to ultraviolet (UV) radiation and chemical toxins. If left unaddressed, DNA damage can lead to mutations, genomic instability, and potentially cell death, thereby contributing to a variety of diseases, including cancer. In response, cells have developed intricate mechanisms referred to as the DNA damage response (DDR) to detect and repair such damages. These mechanisms are vital for maintaining genomic stability and cellular homeostasis.
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Research utilizing cell cultures, animal models, and human tumors has demonstrated that the accumulation of DNA damage, coupled with a decline in DNA repair capabilities, contributes significantly to cancer development. This understanding has facilitated the identification of therapeutic targets aimed at treating various cancers by inducing DNA damage.
Fig. 1 Types of DNA damage (Röthlisberger P., et al. 2019).
Types of DNA Damage
DNA damage can occur due to various endogenous factors, such as replication stress and reactive oxygen species (ROS), and exogenous agents, including ultraviolet (UV) radiation, ionizing radiation, chemotherapeutics, and chemical toxins. These factors can induce a range of DNA lesions, including single-strand breaks (SSBs), double-strand breaks (DSBs), base damage, DNA crosslinks, and clustered damage sites. Among these, DSBs are the most lethal, as failure to repair them can lead to tumorigenesis and cell death.
Cells experience an estimated 70,000 instances of DNA damage daily, with SSBs accounting for about 75% of these events. SSBs can arise from oxidative damage or base hydrolysis processes and can transform into DSBs if not properly repaired. Oxidative damage, in particular, results in extensive base and sugar modifications, such as the generation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxoG). DNA crosslinks are often induced by chemotherapeutic agents like cisplatin or ionizing radiation, which generate free radicals. "Clustered damage" refers to regions where multiple types of DNA damage occur close together, posing significant challenges for the repair processes.
Understanding the DNA Damage Response
Cells have developed a sophisticated DNA damage response (DDR) system to counter various types of DNA damage. DDR includes processes such as cell cycle arrest, DNA repair, and the regulation of DNA replication, and it determines whether a damaged cell will survive or undergo death or senescence. Key DNA repair pathways include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double-strand break repair (DSBR), which encompasses homologous recombination (HR) and non-homologous end joining (NHEJ). Disruptions in DDR can lead to mutations, cellular transformations, or apoptosis, increasing the risk of cancer. Understanding DDR is crucial for cancer therapy, as it provides potential targets for drug development.
BER is a conserved mechanism that repairs single-strand breaks and various base lesions to maintain genomic integrity. The pathway involves DNA glycosylases that remove damaged bases, creating abasic sites. These sites are further processed by enzymes like AP endonuclease (APE1) and DNA polymerases, which fill in the gaps with new nucleotides. BER is crucial for survival under genotoxic stress and interacts with other DNA repair pathways.
NER is more complex, addressing bulky DNA lesions, such as those caused by UV radiation. This pathway involves over 30 proteins and operates through a "cut-and-paste" mechanism to replace damaged DNA segments. NER can be transcription-coupled (TCR-NER) or global (GGR-NER), depending on where the damage occurs in the genome.
MMR is essential for correcting errors that occur during DNA replication, such as mismatched base pairs and small insertions or deletions. The MutS-α complex recognizes these errors, and the MutL-α complex coordinates the excision and replacement of the faulty DNA segment. MMR also plays a role in suppressing homologous recombination and signaling DNA damage.
DSBR is critical for repairing double-strand breaks, the most severe type of DNA damage. HR is an accurate repair method that uses a homologous template, while NHEJ is quicker but more error-prone, often leading to small mutations. These pathways, along with alternative mechanisms like alt-EJ, are essential for preventing chromosomal translocations and maintaining cellular health.
Targeting DNA Damage Repair for Anticancer Therapy
Given the crucial role of DDR in cancer development, targeting DDR pathways has emerged as an attractive strategy for anticancer therapy. Several inhibitors targeting key proteins in DDR pathways have been developed and are currently being explored in clinical trials.
PARP1 Inhibitors
The PARP family, especially PARP1, plays a critical role in DNA damage repair. Inhibitors such as olaparib, talazoparib, niraparib, rucaparib, and velaparib have received FDA approval for cancer therapy. PARP inhibitors exploit the concept of synthetic lethality, particularly in cells with BRCA gene deficiencies, leading to the accumulation of DSBs and subsequent cell death. These inhibitors can also function as sensitizers when combined with other therapies, such as radiation and chemotherapy.
ATM/ATR Inhibitors
ATM and ATR are key kinases involved in DDR. Their inhibitors, including KU-55933, M6620, AZD6738, and BAY1895344, have shown promise in enhancing the sensitivity of cancer cells to DNA-damaging agents, thereby improving therapeutic outcomes. These inhibitors are particularly effective in cancers with defective HR repair mechanisms.
DNA-PK Inhibitors
DNA-PK inhibitors, such as NU7441, nedisertib, and AZD7648, target the NHEJ pathway. These inhibitors enhance the efficacy of radiation and chemotherapy by preventing the repair of DSBs, thereby increasing cancer cell susceptibility to treatment.
CHK1/2 and WEE1 Inhibitors
CHK1 and CHK2, along with WEE1, are critical regulators of cell cycle checkpoints. Inhibitors of these kinases, including AZD7762, rabusertib, and adavosertib (AZD1775), abrogate checkpoint responses, leading to enhanced sensitivity to DNA-damaging agents and promoting cancer cell death.
DNA Pol β and ERCC1 Inhibitors
DNA Pol β is essential for BER and alt-EJ pathways, making it a promising target for cancer therapy. Recent inhibitors have shown potential in preclinical studies. Similarly, targeting ERCC1, a key component of the NER pathway, can enhance the efficacy of platinum-based chemotherapy by preventing the repair of DNA crosslinks, thereby increasing cancer cell sensitivity to treatment.
Conclusion
Understanding the mechanisms of DNA damage and repair is crucial for developing effective cancer therapies. The DDR pathways play a pivotal role in maintaining genomic stability, and targeting key proteins involved in these pathways offers promising opportunities for cancer treatment. Combining DDR inhibitors with traditional chemotherapy and radiation therapy has the potential to enhance treatment effectiveness and improve patient outcomes. As research continues, precision-targeted therapy based on DDR inhibitors is expected to significantly advance cancer treatment, offering new hope for patients.
References
- Wang R., et al. Targeting the DNA damage response for cancer therapy. International Journal of Molecular Sciences. 2023, 24 (21): 15907.
- Alhmoud J. F., et al. DNA damage/repair management in cancers. Advances in Medical Biochemistry, Genomics, Physiology, and Pathology. 2021, 309-39.
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