中国P站

DNA damage; DNA repair; Cancer therapy; Aging; Neurodegeneration; Genomic instability; PARP inhibitors; CRISPR-Cas; Oxidative DNA damage; Cell cycle checkpoints

Introduction

Maintaining genomic integrity is fundamental for cellular function and organismal health, a task critically managed by intricate DNA damage response (DDR) and repair pathways. A comprehensive overview of these pathways, including nucleotide excision repair, base excision repair, mismatch repair, homologous recombination, and non-homologous end joining, reveals their vital roles in counteracting various forms of DNA damage. Impaired DNA repair mechanisms have significant implications for disease development, particularly cancer, and are increasingly targets for therapeutic intervention [1].

The therapeutic landscape in cancer is profoundly influenced by the interplay between DDR pathways and anti-cancer drugs. Understanding how existing agents target specific DDR components, and exploring emerging strategies such as synthetic lethality approaches, is crucial. Developing personalized cancer therapies hinges on exploiting DNA repair vulnerabilities and recognizing specific DDR defects unique to different tumor types [2].

Beyond cancer, the critical role of DDR and repair extends into the context of aging and the pathogenesis of age-related diseases. A decline in the efficiency of DNA repair directly contributes to genomic instability, a recognized hallmark of aging. This decline has far-reaching consequences, contributing to conditions such as neurodegenerative diseases, cardiovascular diseases, and various cancers. Interventions aimed at bolstering these pathways offer promising avenues to combat age-related decline [3].

Further exploring the link between DNA damage, repair mechanisms, and neurodegenerative diseases reveals how compromised DNA repair leads to neuronal dysfunction and cell death. These processes are central to the pathology of conditions like Alzheimer's, Parkinson's, and Huntington's diseases. Investigating specific DNA repair pathways, their dysregulation in the aging brain, and potential therapeutic strategies to enhance DNA repair capacity is vital for mitigating neurodegeneration [4].

A key development in cancer treatment involves Poly (ADP-ribose) polymerase (PARP) inhibitors. These drugs specifically target DNA damage repair pathways, particularly in the context of homologous recombination deficiency. Their mechanism involves trapping PARP on DNA and inducing synthetic lethality, especially with BRCA mutations. The clinical application of PARP inhibitors across various cancer types, along with discussions on efficacy, resistance mechanisms, and optimal patient selection for combination therapies, marks a significant advance [5].

Oxidative DNA damage represents a common and highly relevant type of DNA lesion. Cellular mechanisms dedicated to its repair, primarily through pathways like base excision repair (BER), are essential, particularly concerning cancer. The formation of various oxidative DNA adducts and their removal are critical processes. Dysregulation in the repair of oxidative DNA damage plays a role in carcinogenesis and contributes to drug resistance, prompting exploration of therapeutic strategies to target these pathways to improve cancer treatment outcomes [6].

Cellular surveillance systems, known as DNA damage checkpoints, are indispensable. These checkpoints detect DNA lesions and effectively halt cell cycle progression, allowing time for proper repair. Key kinases, such as ATM and ATR, act as central transducers, becoming activated by different types of DNA damage and initiating downstream signaling cascades that coordinate cell cycle arrest, DNA repair, and even apoptosis. These checkpoints are fundamentally important in preventing genomic instability, making them highly relevant in cancer biology and therapy [7].

The advent of CRISPR-Cas gene editing tools introduces a fascinating interaction with endogenous DNA repair pathways, notably non-homologous end joining (NHEJ) and homologous recombination (HR). These natural repair mechanisms significantly influence the outcomes of CRISPR-induced DNA breaks, determining whether precise edits or undesirable off-target mutations occur. Modulating these DNA repair pathways to enhance the efficiency and specificity of gene editing is a critical area of research for safe and effective genome engineering [8].

Transcription-Coupled DNA Repair (TCR) represents a specialized sub-pathway of nucleotide excision repair (NER), selectively removing lesions from the transcribed strand of active genes. The stalling of RNA Polymerase II at sites of DNA damage acts as a crucial signal for TCR initiation, recruiting essential factors like CSB and CSA. The molecular mechanisms that coordinate transcription with repair are vital, highlighting the physiological importance of TCR in preventing transcription blockage and its implications for human diseases, including inherited disorders and cancer [9].

Finally, the unique aspects of mitochondrial DNA (mtDNA) damage and its repair mechanisms contrast significantly with those of nuclear DNA. Mitochondrial DNA is highly susceptible to oxidative damage due to its close proximity to the electron transport chain. Specific pathways, such as base excision repair (BER) and direct reversal, are involved in mtDNA repair. Defects in these processes contribute to mitochondrial dysfunction, accelerating aging and contributing to the pathogenesis of various human diseases, including metabolic disorders and neurodegeneration [10].

Description

DNA damage is a constant threat to genomic integrity, necessitating robust and intricate repair mechanisms across all life forms. These cellular defenses are broadly categorized into several key pathways, each specialized for different types of lesions. Nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end joining (NHEJ) are critical examples, working in concert to mend DNA breaks and adducts. Understanding these molecular pathways is fundamental, as their efficiency directly correlates with cellular health and the prevention of various pathologies [1].

The implications of compromised DNA repair are particularly stark in cancer. Defective DNA damage response (DDR) pathways not only contribute to the initial development of malignancies but also influence tumor progression and resistance to therapy. Researchers actively explore how existing anti-cancer drugs exert their effects by targeting DDR components. Emerging strategies, such as synthetic lethality, which exploits specific repair vulnerabilities, hold immense promise for personalized cancer treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors, for instance, are a prime example of drugs that leverage homologous recombination deficiency, especially in BRCA-mutated cancers, by trapping PARP on DNA. This therapeutic approach has revolutionized treatment for several cancer types, though understanding resistance mechanisms remains a crucial area of study [2, 5]. Moreover, oxidative DNA damage, a common type of lesion, is particularly relevant in cancer. Pathways like base excision repair are critical for removing oxidative adducts, and dysregulation in this process contributes to carcinogenesis and drug resistance, highlighting potential therapeutic targets [6].

Beyond oncology, the impact of DNA repair deficiencies is profoundly felt in the context of aging and neurodegenerative diseases. Genomic instability, a hallmark of aging, is largely driven by a progressive decline in DNA repair efficiency. This decline plays a pivotal role in the pathogenesis of age-related conditions, including not only cancer but also neurodegenerative disorders like Alzheimer's, Parkinson's, and Huntington's diseases, as well as cardiovascular diseases [3]. In the aging brain, impaired DNA repair contributes directly to neuronal dysfunction and death. Therapeutic strategies focused on enhancing DNA repair capacity in these vulnerable cells represent a promising frontier for mitigating neurodegeneration [4]. A unique and vital aspect of this broader picture is mitochondrial DNA (mtDNA). Highly susceptible to oxidative damage due to its proximity to the electron transport chain, mtDNA has its own specific repair mechanisms, predominantly base excision repair and direct reversal. Defects in these processes lead to mitochondrial dysfunction, a key contributor to aging and a range of diseases from metabolic disorders to neurodegeneration [10].

The cellular machinery for maintaining genomic stability extends beyond direct repair pathways to include sophisticated surveillance systems. DNA damage checkpoints, for example, are essential components that detect DNA lesions and transiently halt the cell cycle, allowing ample time for repair or initiating apoptosis if damage is irreparable. Key kinases like ATM and ATR serve as central transducers in these checkpoints, coordinating a complex signaling cascade. The proper functioning of these checkpoints is crucial for preventing genomic instability and is highly relevant to cancer biology and therapeutic interventions [7]. Furthermore, specialized repair processes such as transcription-coupled DNA repair (TCR), a sub-pathway of nucleotide excision repair, focus on removing lesions from actively transcribed genes. The stalling of RNA Polymerase II at damaged sites acts as a signal for TCR initiation, recruiting factors like CSB and CSA, which ensures gene expression can continue unimpeded. This specialized repair pathway is vital for preventing transcription blockage and has implications for various human diseases [9].

Finally, advancements in genome engineering technologies, particularly CRISPR-Cas systems, have brought new attention to the intrinsic DNA repair pathways. The outcomes of CRISPR-induced DNA breaks are heavily influenced by endogenous repair mechanisms like non-homologous end joining (NHEJ) and homologous recombination (HR). Understanding this intricate interplay is crucial for achieving precise gene edits and minimizing off-target mutations. Modulating these natural repair pathways presents an exciting opportunity to enhance the efficiency and specificity of gene editing, paving the way for safer and more effective therapeutic applications in the future [8].

Conclusion

The provided reviews collectively explore the critical field of DNA damage response (DDR) and repair, essential for maintaining genomic integrity. These articles detail various molecular pathways, including nucleotide excision repair, base excision repair, mismatch repair, homologous recombination, and non-homologous end joining. Beyond fundamental mechanisms, the collection examines the profound implications of impaired DNA repair in the pathogenesis of diverse human diseases. A significant focus is on cancer, where DDR defects contribute to disease development, progression, and drug resistance. Several articles highlight therapeutic strategies, such as Poly (ADP-ribose) polymerase (PARP) inhibitors, which target DNA repair vulnerabilities and exploit synthetic lethality, particularly in BRCA-mutated cancers. The reviews also discuss the potential for personalized cancer therapies by understanding specific DDR defects. The scope extends to aging and age-related conditions, including neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's. Here, declining DNA repair efficiency leads to genomic instability, a hallmark of aging and a driver of neuronal dysfunction. Specific repair pathways, like transcription-coupled DNA repair and mitochondrial DNA repair, are also detailed, emphasizing their unique roles and susceptibility to damage, particularly oxidative stress. Furthermore, the interplay between CRISPR-Cas gene editing and endogenous DNA repair pathways is explored, offering insights into enhancing genome engineering precision. Finally, the role of DNA damage checkpoints, vital cellular surveillance systems, in coordinating cell cycle arrest and repair to prevent genomic instability, is elucidated. This body of work underscores the multifaceted importance of DNA repair in health and disease.

References

1. Ajay KP, Rakesh M, Bijay PM (2021) .Int J Mol Sci 22:10565.

   , ,

2. Xin L, Chang L, Jia L (2022) .Cell Death Dis 13:6.

   , ,

3. Yan L, Shanshan Z, Shan S (2023) .Int J Mol Sci 24:507.

   , ,

4. Wenjuan L, Xiujuan W, Jin S (2020) .Front Cell Neurosci 14:571695.

   , ,

5. Spiros B, Niki K, Christina T (2021) .Cancers (Basel) 13:137.

   , ,

6. Li Y, Bin T, Guiqin W (2023) .Front Pharmacol 14:1114560.

   , ,

7. Marco G, Andrea P, Sara S (2021) .Semin Cell Dev Biol 110:1-13.

   , ,

8. Debora E, Massimo C, Angelica G (2022) .Cell Death Differ 29:267-281.

   , ,

9. Xiaojie H, Ying Z, Wen L (2022) .Int J Mol Sci 23:6023.

   , ,

10. Jia L, Wenting W, Yan L (2023) .Int J Mol Sci 24:3521.

    , ,