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This report is written by MaltSci based on the latest literature and research findings

What are the mechanisms of DNA repair? ​

Abstract ​

DNA repair is a vital biological process that preserves the integrity of genetic information, playing a key role in cellular homeostasis and organismal stability. Throughout an organism's life, DNA is constantly subjected to various damaging agents, both endogenous and exogenous, leading to mutations and genomic instability. Understanding the mechanisms of DNA repair is crucial for advancing cellular biology and developing therapeutic strategies to mitigate the consequences of DNA damage. This review provides a comprehensive overview of the major DNA repair pathways, including 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). Each pathway involves intricate molecular components and regulatory networks that ensure efficient repair of DNA lesions. We explore the types and sources of DNA damage, the specific mechanisms of repair, and the regulatory processes that govern these pathways, including checkpoint signaling and post-translational modifications. The implications of DNA repair mechanisms in human health and disease are examined, highlighting their roles in cancer development, aging, and genetic disorders. Recent advances in DNA repair research are discussed, showcasing novel therapeutic approaches and gene editing technologies that leverage our understanding of these pathways. By elucidating the mechanisms of DNA repair, this review aims to enhance our understanding of genomic integrity maintenance and pave the way for future therapeutic innovations.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Overview of DNA Damage
    • 2.1 Types of DNA Damage
    • 2.2 Sources of DNA Damage
  • 3 Mechanisms of DNA Repair
    • 3.1 Base Excision Repair (BER)
    • 3.2 Nucleotide Excision Repair (NER)
    • 3.3 Mismatch Repair (MMR)
    • 3.4 Double-Strand Break Repair
    • 3.5 3.4.1 Homologous Recombination (HR)
    • 3.6 3.4.2 Non-Homologous End Joining (NHEJ)
  • 4 Regulation of DNA Repair Pathways
    • 4.1 Checkpoint Signaling
    • 4.2 Post-Translational Modifications
  • 5 Implications of DNA Repair in Health and Disease
    • 5.1 Cancer Development
    • 5.2 Aging and Genetic Disorders
  • 6 Recent Advances in DNA Repair Research
    • 6.1 Novel Therapeutic Approaches
    • 6.2 Gene Editing Technologies
  • 7 Summary

1 Introduction ​

DNA repair is a fundamental biological process that safeguards the integrity of genetic information, playing a crucial role in maintaining cellular homeostasis and organismal stability. Throughout an organism's life, its DNA is constantly exposed to a myriad of damaging agents, both endogenous—such as reactive oxygen species generated during metabolic processes—and exogenous, including environmental toxins and ionizing radiation. The inability to effectively repair DNA damage can lead to mutations, genomic instability, and the onset of various diseases, most notably cancer. As such, understanding the mechanisms underlying DNA repair is vital not only for advancing our knowledge of cellular biology but also for developing innovative therapeutic strategies aimed at mitigating the consequences of DNA damage.

The significance of DNA repair mechanisms extends beyond mere cellular maintenance; they are intricately linked to numerous physiological processes, including aging, immune response, and developmental biology. For instance, defects in DNA repair pathways are associated with a range of hereditary disorders and contribute to the pathogenesis of various cancers, including breast, colorectal, and hematological malignancies[1][2][3]. Moreover, emerging evidence suggests that DNA repair pathways play a role in the regulation of immune responses, where the repair of DNA damage is essential for effective immune activation and the maintenance of genomic integrity in immune cells[4].

Current research has elucidated several major DNA repair pathways, including 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). Each of these pathways involves a complex interplay of molecular components and regulatory networks that ensure the precise and efficient repair of DNA lesions. For instance, BER primarily addresses small base modifications, while NER is responsible for the removal of bulky DNA adducts. MMR corrects replication errors, and DSBR is crucial for repairing severe DNA breaks that can occur during DNA replication and as a result of environmental stressors[5][6][7].

This review is organized into several sections that systematically explore the mechanisms of DNA repair. We begin with an overview of DNA damage, detailing the various types and sources of DNA lesions. Following this, we delve into the specific mechanisms of DNA repair, discussing each major pathway in depth, including their molecular components and regulatory aspects. We then examine the regulation of DNA repair pathways, focusing on checkpoint signaling and post-translational modifications that influence repair efficiency. The implications of DNA repair mechanisms in human health and disease are also addressed, with particular attention to their roles in cancer development, aging, and genetic disorders. Recent advances in DNA repair research are highlighted, showcasing novel therapeutic approaches and gene editing technologies that leverage our understanding of these pathways. Finally, we conclude with a summary of key findings and future directions for research in this critical area of biomedical science.

By providing a comprehensive overview of DNA repair mechanisms, this review aims to enhance our understanding of how cells maintain genomic integrity and respond to DNA damage, thereby laying the groundwork for future therapeutic innovations.

2 Overview of DNA Damage ​

2.1 Types of DNA Damage ​

DNA repair mechanisms are essential for maintaining genomic integrity and preventing the accumulation of mutations that can lead to various diseases, including cancer. The primary DNA repair pathways include base excision repair, nucleotide excision repair, mismatch repair, homologous recombination repair, and postreplication repair, each of which addresses different types of DNA damage.

  1. Base Excision Repair (BER): This pathway is responsible for repairing small, non-helix-distorting base lesions resulting from oxidation, alkylation, or deamination. It involves the removal of the damaged base by a DNA glycosylase, followed by the action of an AP endonuclease, DNA polymerase, and DNA ligase to restore the integrity of the DNA strand.

  2. Nucleotide Excision Repair (NER): NER is crucial for repairing bulky DNA adducts, such as those formed by UV radiation. This mechanism involves the excision of a short single-strand segment containing the lesion, which is then filled in by DNA polymerase using the undamaged strand as a template.

  3. Mismatch Repair (MMR): MMR corrects errors that escape proofreading during DNA replication, such as base-base mismatches and insertion-deletion loops. This pathway recognizes the mismatch, excises the incorrect section, and resynthesizes the DNA using the correct template.

  4. Homologous Recombination Repair (HRR): HRR is a critical mechanism for repairing double-strand breaks in DNA. It requires an undamaged homologous template (usually the sister chromatid) to accurately repair the break. This process is vital during the S and G2 phases of the cell cycle.

  5. Postreplication Repair (PRR): This pathway allows cells to bypass lesions that block replication. It includes both error-free and error-prone mechanisms. The error-free pathway involves switching to an undamaged template, while the error-prone pathway utilizes specialized translesion synthesis DNA polymerases to replicate across the lesion, albeit with a higher risk of introducing mutations.

The mechanisms of DNA repair are interconnected and often exhibit a high degree of functional redundancy, which minimizes the detrimental effects of DNA damage from both endogenous and exogenous sources. For instance, studies in Saccharomyces cerevisiae have elucidated these highly conserved mechanisms that promote eukaryotic genome stability and underscore the importance of DNA repair in maintaining cellular integrity [5].

Additionally, the loss or dysfunction of these repair pathways is associated with various human diseases, including cancer. For example, defects in mismatch repair have been linked to hereditary non-polyposis colorectal cancer, while deficiencies in nucleotide excision repair are associated with xeroderma pigmentosum, a condition that predisposes individuals to skin cancer due to UV sensitivity [3].

Overall, understanding the diverse DNA repair mechanisms is crucial for developing therapeutic strategies aimed at enhancing genomic stability and combating diseases associated with DNA damage.

2.2 Sources of DNA Damage ​

DNA repair mechanisms are critical for maintaining genomic integrity and preventing mutations that can lead to various diseases, including cancer. The DNA repair processes are complex and consist of several pathways, each specialized for repairing different types of DNA damage. The major mechanisms of DNA repair include:

  1. Base Excision Repair (BER): This pathway primarily addresses small, non-helix-distorting base lesions. It involves the recognition and removal of damaged bases by specific DNA glycosylases, followed by the excision of the resulting abasic site and the synthesis of the correct nucleotide using the complementary strand as a template.

  2. Nucleotide Excision Repair (NER): NER is responsible for removing bulky DNA adducts and helix-distorting lesions, such as those caused by ultraviolet (UV) radiation. The process includes the recognition of the damaged site, unwinding of the DNA, excision of a short single-stranded DNA segment containing the lesion, and resynthesis of the excised strand using the undamaged strand as a template.

  3. Mismatch Repair (MMR): This mechanism corrects errors that occur during DNA replication, such as base-base mismatches and insertion-deletion loops. MMR proteins recognize the mismatches, excise the erroneous segment, and resynthesize the correct DNA sequence.

  4. Double-Strand Break Repair (DSBR): Double-strand breaks (DSBs) are among the most severe forms of DNA damage and can be repaired through two primary pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). HR uses a homologous template for accurate repair, while NHEJ directly ligates the broken ends without the need for a template, which can lead to insertions or deletions.

  5. Postreplication Repair (PRR): This pathway allows the bypass of lesions that block DNA replication. It includes error-free and error-prone mechanisms, with specialized translesion synthesis DNA polymerases facilitating DNA synthesis across the damaged sites.

  6. Translesion Synthesis (TLS): This is a specialized mechanism where specific DNA polymerases synthesize DNA across lesions, albeit often with a higher risk of introducing mutations.

  7. DNA Repair in Gametogenesis: In mammals, DNA repair mechanisms also play a role in gametogenesis, where they not only repair DNA damage but also facilitate meiotic recombination. This is crucial for maintaining genetic diversity and ensuring the integrity of the germline [8].

  8. Role of DNA Repair in Cancer Therapy: The efficiency of DNA repair pathways is significant in the context of cancer therapy, as many anticancer treatments (like radiation and certain chemotherapies) rely on inducing DNA damage to kill cancer cells. However, the ability of cancer cells to repair this damage can lead to resistance against these therapies [2].

Sources of DNA damage can be broadly categorized into endogenous and exogenous factors:

  • Endogenous Sources: These include normal metabolic processes that generate reactive oxygen species (ROS), leading to oxidative damage to DNA. Additionally, errors during DNA replication can introduce mutations.

  • Exogenous Sources: Environmental factors such as UV radiation, ionizing radiation, and chemical agents (e.g., certain drugs, pollutants) can induce various types of DNA lesions. For example, UV radiation primarily causes the formation of pyrimidine dimers, while ionizing radiation can result in double-strand breaks [3].

In summary, DNA repair mechanisms are diverse and crucial for cellular health, providing pathways to rectify a wide array of DNA lesions caused by both internal and external factors. Understanding these mechanisms not only enhances our knowledge of cellular biology but also informs therapeutic strategies for treating diseases associated with DNA damage, particularly cancer.

3 Mechanisms of DNA Repair ​

3.1 Base Excision Repair (BER) ​

Base excision repair (BER) is a critical DNA repair mechanism that corrects specific types of DNA damage, particularly those resulting from oxidative stress, alkylation, deamination, and other chemical modifications. The BER pathway is essential for maintaining genomic stability, as it is responsible for repairing non-helix-distorting base lesions and single-strand breaks. This process is initiated by the recognition and removal of damaged bases, followed by a series of coordinated enzymatic reactions.

The BER mechanism typically involves five sequential steps:

  1. Base Removal: The process begins with the recognition of a damaged base by a specific DNA glycosylase, which catalyzes the cleavage of the N-glycosidic bond, leading to the release of the damaged base and the formation of an abasic (AP) site.

  2. Incision: The resulting abasic site is then incised by an apurinic/apyrimidinic endonuclease, which creates a single-strand break in the DNA backbone.

  3. Processing of Termini: The ends of the DNA strand at the break are processed to create a suitable substrate for DNA synthesis. This may involve the action of various enzymes that prepare the DNA ends for repair synthesis.

  4. DNA Synthesis: DNA polymerase, often DNA polymerase β, fills in the gap by synthesizing new DNA to replace the missing nucleotide(s). This step is crucial for restoring the integrity of the DNA molecule.

  5. Ligation: Finally, DNA ligase seals the nick in the DNA backbone, completing the repair process and restoring the DNA to its original state.

The BER pathway can be further categorized into two sub-pathways: short-patch and long-patch BER. The short-patch BER pathway typically results in the replacement of a single nucleotide, while the long-patch BER pathway can replace multiple nucleotides (at least two) and involves additional factors such as PCNA (proliferating cell nuclear antigen) and FEN1 (flap endonuclease 1) to facilitate the repair process [9].

The significance of BER is underscored by its association with various diseases, including cancer and aging. Defects in BER can lead to the accumulation of DNA damage, which may result in genomic instability and increased susceptibility to malignancies [10]. Additionally, recent studies have highlighted the dynamic interactions between BER proteins and their regulatory mechanisms, emphasizing the importance of tight control over enzyme levels and activity in maintaining genomic integrity [11].

In summary, BER is a sophisticated and highly conserved DNA repair mechanism that plays a pivotal role in cellular maintenance and the prevention of diseases associated with DNA damage. The interplay of various proteins and the coordination of multiple enzymatic steps are crucial for the effective repair of DNA lesions and the preservation of genomic stability [12].

3.2 Nucleotide Excision Repair (NER) ​

Nucleotide excision repair (NER) is a crucial DNA repair mechanism that maintains genomic integrity by removing a wide variety of helix-distorting DNA lesions. These lesions can arise from various sources, including ultraviolet (UV) radiation, environmental mutagens, and certain chemotherapeutic agents. NER operates through a multi-step process that can be broadly categorized into two sub-pathways: global genome NER (GG-NER) and transcription-coupled NER (TC-NER).

GG-NER is responsible for identifying and repairing DNA damage throughout the entire genome, primarily to prevent the accumulation of mutations. In contrast, TC-NER specifically targets lesions in the transcribed strand of active genes, thereby ensuring the continuity of transcription by RNA polymerase II. This sub-pathway is particularly vital as it rapidly repairs DNA damage that would otherwise lead to cell death due to transcriptional blockage [13].

The NER process involves several key steps, starting with damage recognition, followed by dual incisions flanking the lesion, excision of the damaged DNA strand, and finally, synthesis of new DNA to fill the gap left by the excised segment. This process requires a coordinated action of numerous proteins, including damage recognition factors such as XPC and DDB2, which initiate the repair by recognizing the distortions in the DNA helix [14].

Recent studies have illuminated the intricate regulatory mechanisms that govern NER. These include transcriptional and post-translational modifications that influence the activity and capacity of the NER pathway. For instance, the abundance of NER proteins, such as ERCC1, can affect the decision between DNA repair and apoptosis upon DNA damage, highlighting the pathway's dual role in maintaining genomic integrity and regulating cell fate [15].

Furthermore, defects in NER are linked to several genetic disorders, most notably xeroderma pigmentosum (XP), which is characterized by extreme sensitivity to UV light and a predisposition to skin cancers. XP results from mutations in genes responsible for NER, emphasizing the pathway's critical role in protecting against environmental DNA damage [16].

The understanding of NER has advanced significantly, with insights into its mechanism, protein interactions, and the impact of chromatin context on repair efficiency. This evolving knowledge not only enhances our comprehension of fundamental cellular processes but also opens avenues for therapeutic interventions in conditions associated with NER deficiencies [17][18].

In summary, NER is a vital DNA repair mechanism characterized by its ability to remove a broad spectrum of DNA lesions through a highly regulated process involving multiple proteins and pathways. Its significance is underscored by the severe consequences associated with its dysfunction, including cancer and accelerated aging [13][19].

3.3 Mismatch Repair (MMR) ​

DNA mismatch repair (MMR) is a critical mechanism that maintains genomic integrity by correcting replication errors, thereby preventing mutations that could lead to various diseases, including cancer. The MMR system detects and repairs non-Watson-Crick base pairs and strand misalignments that occur during DNA replication. The process involves several key steps and proteins that work in concert to ensure accurate DNA replication.

The initiation of MMR is primarily carried out by the MutS protein, which recognizes the mismatch. In humans, two complexes, Msh2-Msh6 and Msh2-Msh3, serve as the primary mismatch repair initiation factors. These complexes are responsible for identifying DNA lesions and initiating the repair process. The Msh2-Msh6 complex specifically recognizes base-base mispairs, while the Msh2-Msh3 complex is adept at recognizing insertion or deletion loops up to approximately 17 nucleotides [20].

Once a mismatch is recognized, the MMR system must distinguish the newly synthesized strand from the parental strand. This strand discrimination is crucial, as it ensures that only the erroneous strand is removed and re-synthesized. Recent studies have elucidated the role of the MutL protein in this discrimination process, which involves biochemical, biophysical, and structural analyses. MutL aids in marking the newly synthesized strand for removal, facilitating the subsequent steps of the repair process [21].

Following the identification and marking of the mismatch, the repair process continues with the excision of the erroneous strand. This is mediated by a series of enzymatic activities that remove the mismatch-containing tract of nascent DNA. The excised region is then resynthesized accurately, thus restoring the fidelity of the genetic material. The MMR system enhances the fidelity of DNA replication by several orders of magnitude, addressing not only errors arising during replication but also those occurring during recombination [22].

Moreover, the MMR system has been implicated in various other biological processes beyond mere error correction. For instance, it plays roles in DNA damage signaling, antibody diversification, and the repair of interstrand cross-links and oxidative DNA damage [22]. This multifaceted nature of MMR highlights its importance not only in maintaining genomic stability but also in influencing other cellular functions.

However, when MMR is deficient, as seen in certain hereditary conditions, it leads to a mutator phenotype characterized by increased mutation rates and genomic instability, which can predispose individuals to cancers, particularly hereditary nonpolyposis colorectal cancer [23]. Understanding the mechanisms of MMR, including the roles of specific proteins and the intricacies of the repair process, is essential for elucidating its contributions to both normal cellular function and disease pathogenesis [24].

In summary, the mechanisms of DNA mismatch repair involve the recognition of mismatches by specific protein complexes, strand discrimination, excision of erroneous DNA, and subsequent resynthesis, all of which are crucial for maintaining genomic integrity and preventing disease.

3.4 Double-Strand Break Repair ​

DNA double-strand breaks (DSBs) are among the most severe types of DNA damage, significantly threatening genomic stability. The repair of DSBs is primarily accomplished through two main pathways: non-homologous end joining (NHEJ) and homologous recombination (HR). Each of these pathways has distinct mechanisms and regulatory processes that facilitate the repair of DSBs.

NHEJ is a predominant repair pathway that operates throughout the cell cycle, particularly in the G1 phase. This process involves the direct ligation of the broken DNA ends without the need for a homologous template. Key proteins in this pathway include the Ku70/80 heterodimer, which binds to the DNA ends, and DNA-PKcs, which is recruited to form a complex that stabilizes the ends and facilitates their alignment for ligation. The enzymes involved in NHEJ are critical for ensuring the efficient and accurate repair of DSBs, as any errors during this process can lead to genomic instability, potentially resulting in cell death or oncogenesis [25].

In contrast, HR is typically active during the S and G2 phases of the cell cycle, when a sister chromatid is available as a template for repair. This pathway is generally considered to be error-free due to its reliance on homologous sequences for accurate repair. The process begins with the resection of the 5' ends of the DSB, which is essential for the formation of single-stranded DNA (ssDNA) that can invade the homologous template. Proteins such as RAD51 play a pivotal role in this strand invasion and subsequent repair synthesis [26].

Recent studies have revealed that HR, once thought to be an exclusively error-free process, can also exhibit mutagenic properties, particularly in scenarios requiring extensive DNA synthesis. This has implications for the understanding of genomic changes associated with cancer and congenital disorders, where error-prone repair mechanisms may lead to chromosomal translocations and other complex rearrangements [27].

The repair of DSBs is regulated by several factors, including the MRN complex (MRE11-RAD50-NBS1), which is crucial for the initial recognition of DSBs and the recruitment of repair proteins. The MRN complex activates the ATM kinase, which in turn activates other key proteins involved in both signaling and repair, such as BRCA1/2 and ATR [28]. The choice between NHEJ and HR is influenced by the cell cycle stage and the specific cellular context, highlighting the intricate regulatory mechanisms that dictate DSB repair pathway selection [29].

Furthermore, the concept of liquid-liquid phase separation (LLPS) has emerged as an important mechanism in the formation of repair centers at DSB sites. This phenomenon facilitates the concentration of repair factors, thereby enhancing the efficiency of the repair process [30].

In summary, the mechanisms of DNA double-strand break repair are complex and involve a coordinated interplay between various proteins and pathways. NHEJ provides a rapid, albeit error-prone, repair option, while HR offers a more accurate repair strategy that is critical for maintaining genomic integrity. Understanding these mechanisms is essential for developing targeted therapies, particularly in the context of cancer treatment, where exploiting specific vulnerabilities in DSB repair pathways may enhance the efficacy of DNA-damaging agents [31].

3.5 .1 Homologous Recombination (HR) ​

Homologous recombination (HR) is a critical DNA repair mechanism that plays a vital role in maintaining genomic integrity by accurately repairing DNA double-strand breaks (DSBs). The HR process involves several key steps and components, which ensure effective repair while minimizing genomic instability.

At the core of HR is the recognition and utilization of a homologous DNA template to guide the repair process. This begins with the resection of the DSB ends to create 3' single-stranded DNA (ssDNA) overhangs. A recombinase protein, primarily Rad51 in eukaryotes, assembles onto the ssDNA, forming a nucleoprotein filament that promotes the pairing of the ssDNA with a homologous duplex DNA sequence. This pairing is facilitated by a process known as the homology search, which consists of a collision step and a selection step, allowing for homologous pairing between matching DNA sequences [32].

The subsequent strand invasion step involves the ssDNA invading the homologous duplex, leading to the formation of a displacement loop (D-loop). This intermediate is crucial for the synthesis of new DNA, which extends from the 3' end of the invading strand, effectively repairing the break. The resolution of the extended DNA joint can occur through several pathways, restoring the integrity of the chromosome [33].

HR is tightly regulated, as dysregulation can lead to genomic instability, contributing to cancer development. Mutations in genes associated with HR, such as BRCA1 and BRCA2, significantly increase the risk of cancers like breast and ovarian cancer, as they are essential for maintaining the fidelity of the HR process [34]. Furthermore, the regulation of HR is influenced by various post-translational modifications, such as sumoylation, which can modulate the activity and stability of HR proteins [35].

In addition to repairing DSBs, HR also plays a role in resolving replication fork stalling and protecting telomeres, thus ensuring overall genomic stability [36]. The failure to properly execute HR can lead to deleterious consequences, including loss of heterozygosity and genomic rearrangements, further underscoring the importance of this repair pathway [37].

Overall, homologous recombination is a sophisticated and essential mechanism for DNA repair, relying on a coordinated interplay of various proteins and regulatory mechanisms to maintain genomic integrity and prevent tumorigenesis.

3.6 .2 Non-Homologous End Joining (NHEJ) ​

Non-homologous end joining (NHEJ) is a critical DNA repair mechanism that primarily functions to repair double-strand breaks (DSBs) in DNA. It operates throughout the cell cycle and is especially vital in cells such as lymphocytes, which rely on this pathway for the rearrangement of antigen receptor genes. The NHEJ process involves several key proteins and structural components that work together to accurately and efficiently repair DSBs.

The NHEJ mechanism can be divided into several stages: recognition of the DSB, synapsis (juxtaposition of the broken DNA ends), end processing, and ligation. The initial recognition of DSBs is mediated by the Ku70/80 heterodimer, which binds to the DNA ends and recruits other essential factors, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), X-ray cross-complementing protein 4 (XRCC4), XRCC4-like factor (XLF), and DNA ligase IV [38][39][40].

During the synapsis phase, the two ends of the DSB are brought together. This step is crucial because the subsequent repair steps depend on the accurate alignment of the DNA ends. Recent studies have highlighted that synapsis can occur through various mechanisms, and the precise positioning of the DNA ends is achieved through dynamic interactions between the proteins involved [39][40].

Once the ends are aligned, the end processing step may occur, which involves the trimming or modification of the DNA ends to facilitate ligation. The ligation step is performed by DNA ligase IV, which is assisted by XRCC4 and XLF. This complex forms a bridge that facilitates the joining of the DNA ends [41][42].

NHEJ is characterized by its imprecision, which allows for the introduction of small insertions or deletions at the site of repair. This property is particularly advantageous for immune cells, as it contributes to the diversity of antigen receptors. However, the imprecise nature of NHEJ can also lead to genetic changes that may predispose cells to cancer [43].

In summary, NHEJ is a multifaceted DNA repair pathway that involves a series of well-coordinated steps: recognition of DSBs, synapsis, end processing, and ligation. The participation of multiple proteins ensures that DSBs are repaired efficiently, although the mechanism's inherent imprecision can have both beneficial and detrimental consequences for cellular function and genome stability [38][39][41].

4 Regulation of DNA Repair Pathways ​

4.1 Checkpoint Signaling ​

DNA repair mechanisms are critical for maintaining genomic integrity and involve a complex interplay of various pathways that are tightly regulated by checkpoint signaling. The regulation of DNA repair pathways is particularly important during the cell cycle, as cells must coordinate repair processes with cell division to prevent the propagation of DNA damage.

The DNA damage response (DDR) encompasses a series of cellular processes that detect DNA damage, activate repair mechanisms, and regulate cell cycle progression. Checkpoint signaling pathways play a pivotal role in this response by temporarily halting the cell cycle to allow for DNA repair. The primary signaling molecules involved in these checkpoints include ATM (ataxia telangiectasia mutated), ATR (ATM- and Rad3-related), Chk1, and Chk2, which respond to various forms of DNA damage, such as double-strand breaks (DSBs) and replication stress [44][45][46].

When DNA damage occurs, checkpoint proteins are activated to initiate a signaling cascade that leads to cell cycle arrest. For instance, ATM and ATR are activated by DSBs and replication stress, respectively, and subsequently phosphorylate downstream targets such as Chk1 and Chk2. This phosphorylation results in the inhibition of cell cycle progression, allowing time for DNA repair mechanisms to act [44][47].

The main DNA repair pathways include homologous recombination (HR) and non-homologous end joining (NHEJ), both of which are crucial for repairing DSBs. HR is typically more accurate and is often employed during the S and G2 phases of the cell cycle when a sister chromatid is available as a template for repair. In contrast, NHEJ operates throughout the cell cycle and is utilized when HR is not feasible, such as in G1 phase [48][49].

Additionally, during the S phase, the intra-S-phase checkpoint is activated in response to replication stress. This checkpoint involves proteins such as Tof1 and Mrc1, which form a replication-pausing complex that stabilizes the replication fork and facilitates DNA repair [47][47]. The coordination of checkpoint signaling and repair mechanisms ensures that cells do not proceed through the cell cycle with unresolved DNA damage, thereby preventing genomic instability and the potential development of cancer [44][48].

Furthermore, the regulation of checkpoint signaling is crucial for recovery from DNA damage. Once the damage is repaired, cells must downregulate checkpoint signaling to resume normal cell cycle progression. This recovery process involves a complex network of signals, including the Ras signaling pathway, which has been shown to regulate checkpoint recovery in budding yeast [50].

In summary, the mechanisms of DNA repair are intricately linked to checkpoint signaling pathways that regulate cell cycle progression in response to DNA damage. This regulatory framework is essential for maintaining genomic stability and preventing the accumulation of mutations that could lead to cancer. The interplay between DNA repair mechanisms and checkpoint signaling highlights the importance of these processes in cellular responses to genotoxic stress [44][46][48].

4.2 Post-Translational Modifications ​

DNA repair is a crucial cellular process that maintains genome stability and prevents the accumulation of mutations, which can lead to diseases such as cancer. Various mechanisms of DNA repair exist, and these mechanisms are intricately regulated by post-translational modifications (PTMs) of proteins involved in the repair pathways.

Post-translational modifications, including ubiquitination, phosphorylation, acetylation, and sumoylation, play significant roles in the regulation of DNA repair proteins. These modifications can alter the function, localization, and stability of the proteins, thus impacting the overall DNA repair process. For instance, ubiquitination is particularly pivotal in the regulation of DNA double-strand break (DSB) repair pathways. It coordinates the recruitment and removal of repair proteins at the site of damage, thereby fine-tuning the repair process [51].

Specific proteins, such as heterogeneous nuclear ribonucleoprotein K (hnRNP K), have been shown to be involved in DNA damage repair under the influence of various PTMs. hnRNP K undergoes modifications such as methylation, ubiquitination, sumoylation, and phosphorylation, which enhance its regulatory roles in DNA repair mechanisms [52]. Moreover, the role of PTMs is further emphasized by the involvement of DNA damage response kinases, which are critical for sensing DNA damage and orchestrating downstream repair activities [53].

The chromatin landscape also influences DNA repair pathways, as the packaging of DNA into nucleosomes affects the accessibility of repair machinery to damaged sites. Histone PTMs, such as methylation and acetylation, can dictate the choice of repair pathway—whether homologous recombination (HR) or non-homologous end joining (NHEJ)—based on the chromatin state [54]. This is particularly relevant in the context of DSBs, where the cellular response is tailored according to the local chromatin environment.

Furthermore, non-coding microRNAs (miRNAs) have emerged as regulators of DNA repair proteins through post-transcriptional modifications, indicating a complex interplay between transcriptional and post-translational regulatory mechanisms in maintaining genomic integrity [55].

In summary, the regulation of DNA repair pathways through post-translational modifications is a multifaceted process that involves various types of modifications, protein interactions, and chromatin dynamics. These mechanisms collectively ensure the effective repair of DNA damage and the maintenance of genome stability in eukaryotic cells.

5 Implications of DNA Repair in Health and Disease ​

5.1 Cancer Development ​

DNA repair mechanisms are critical for maintaining genomic integrity and preventing the onset of diseases, particularly cancer. The complexity of DNA repair involves several pathways, each tailored to address specific types of DNA damage. The four major DNA repair processes include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double-strand break repair, which can occur via homologous recombination (HR) or nonhomologous end joining (NHEJ) [6][56].

  1. Base Excision Repair (BER): This mechanism primarily repairs small, non-helix-distorting base lesions. It involves the recognition and removal of damaged bases by DNA glycosylases, followed by the recruitment of other enzymes to restore the DNA structure [6].

  2. Nucleotide Excision Repair (NER): NER is responsible for repairing bulky DNA adducts and helix-distorting lesions, such as those caused by UV radiation. The process involves the excision of a short single-stranded DNA segment containing the lesion, followed by DNA synthesis to fill the gap [6].

  3. Mismatch Repair (MMR): This pathway corrects base-pair mismatches and insertion-deletion loops that arise during DNA replication. Defects in MMR are associated with increased mutation rates and various cancers, including hereditary non-polyposis colorectal cancer [3].

  4. Double-Strand Break Repair: Double-strand breaks (DSBs) can be repaired by two main pathways: homologous recombination (HR) and nonhomologous end joining (NHEJ). HR is an error-free repair mechanism that uses a homologous template for repair, while NHEJ is a quicker, error-prone process that directly ligates the broken ends [56].

The implications of DNA repair mechanisms in health and disease are profound. Efficient DNA repair is essential for preventing mutations that can lead to cancer. DNA damage, resulting from various factors such as oxidative stress, environmental toxins, and replication errors, can lead to genomic instability, a hallmark of cancer development [57][58]. When DNA repair mechanisms are impaired, the accumulation of mutations increases the risk of tumorigenesis [7][59].

Moreover, recent studies have highlighted the relationship between DNA repair deficiencies and cancer therapy resistance. Tumors often exhibit alterations in DNA repair pathways, which can contribute to their ability to withstand chemotherapy and radiation treatments [60][61]. For instance, tumors with defects in HR may respond differently to PARP inhibitors, a class of drugs designed to exploit these weaknesses in cancer cells [7].

In conclusion, the intricate network of DNA repair mechanisms plays a vital role in maintaining genomic stability and preventing cancer. Understanding these processes not only enhances our knowledge of cancer biology but also paves the way for the development of targeted therapies that exploit the vulnerabilities of cancer cells with defective DNA repair pathways. This approach could lead to more effective treatment strategies for patients with various types of cancer.

5.2 Aging and Genetic Disorders ​

DNA repair mechanisms are essential for maintaining genomic stability and protecting cells from the detrimental effects of DNA damage, which can arise from both intrinsic and extrinsic factors. The primary DNA repair mechanisms include base excision repair, nucleotide excision repair, mismatch repair, and double-strand break repair, each of which involves a series of complex and coordinated processes to detect and rectify DNA lesions.

Base excision repair (BER) is responsible for repairing small, non-helix-distorting base lesions resulting from oxidative stress, alkylation, or deamination. This process involves the recognition and removal of the damaged base by specific glycosylases, followed by the recruitment of endonucleases and DNA polymerases to fill the gap and restore the DNA strand [6].

Nucleotide excision repair (NER) is crucial for removing bulky DNA adducts and helix-distorting lesions, such as those caused by ultraviolet (UV) radiation. This mechanism involves the recognition of the damaged DNA segment, excision of a short single-stranded DNA segment containing the lesion, and subsequent resynthesis of the excised strand [62].

Mismatch repair (MMR) is a system that corrects errors that escape proofreading during DNA replication, such as base-base mismatches and insertion-deletion loops. The MMR pathway enhances the fidelity of DNA replication and is vital for preventing mutations that can lead to cancer [63].

Double-strand break repair (DSBR) is particularly critical, as breaks in both strands of the DNA can lead to genomic instability and cell death if not repaired properly. DSBR can occur through two main pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). HR uses a homologous template for accurate repair, while NHEJ directly joins the broken ends, which can sometimes lead to mutations [64].

The implications of DNA repair mechanisms in health and disease are profound. Deficiencies in these repair pathways are closely associated with various genetic disorders and age-related diseases. For instance, inherited defects in DNA repair proteins can lead to syndromes characterized by increased cancer susceptibility, such as Xeroderma pigmentosum, which is linked to defective nucleotide excision repair [7]. Additionally, research has shown that aging is accompanied by a decline in DNA repair efficiency, contributing to the accumulation of DNA damage and the onset of age-related diseases [61].

Moreover, DNA repair mechanisms have been implicated in the development of cancer. Mutations in genes involved in DNA repair can lead to genomic instability, a hallmark of cancer cells. The relationship between DNA repair defects and cancer has been extensively studied, revealing that certain types of cancers, including breast and colorectal cancers, are associated with specific DNA repair deficiencies [3].

Recent findings suggest that DNA repair also plays a role in cellular aging and the functionality of adult stem cells. A decline in DNA repair capacity can limit the regenerative potential of stem cells, thereby affecting tissue maintenance and longevity [65]. This highlights the importance of maintaining efficient DNA repair processes not only for preventing disease but also for promoting healthy aging.

In conclusion, DNA repair mechanisms are critical for preserving genomic integrity and preventing the onset of various diseases, including cancer and age-related disorders. Understanding these mechanisms offers valuable insights into potential therapeutic strategies for enhancing DNA repair and mitigating the impacts of aging and genetic disorders.

6 Recent Advances in DNA Repair Research ​

6.1 Novel Therapeutic Approaches ​

DNA repair mechanisms are essential for maintaining genomic integrity and preventing mutations that can lead to various diseases, including cancer. Recent advances in DNA repair research have identified several key mechanisms and pathways that facilitate the repair of DNA damage, and these findings have opened new avenues for therapeutic interventions.

The primary DNA repair mechanisms can be broadly categorized into several types:

  1. Base Excision Repair (BER): This pathway is crucial for correcting small, non-helix-distorting base lesions resulting from oxidation, alkylation, or deamination. The process involves the recognition and removal of damaged bases by specific glycosylases, followed by the action of DNA polymerases to fill the resulting gaps and ligases to seal the nicks in the DNA strand [6].

  2. Nucleotide Excision Repair (NER): NER is responsible for removing bulky DNA adducts and helix-distorting lesions, such as those caused by UV radiation. This mechanism operates through two sub-pathways: Global Genome Repair (GGR), which surveys the entire genome for damage, and Transcription-Coupled Repair (TCR), which focuses on actively transcribed genes [66].

  3. Mismatch Repair (MMR): MMR corrects errors that occur during DNA replication, such as misincorporated bases and insertion-deletion loops. Deficiencies in this pathway are linked to certain hereditary cancers, highlighting its critical role in maintaining genomic stability [3].

  4. Homologous Recombination (HR): HR is a precise repair mechanism that repairs double-strand breaks (DSBs) using a homologous sequence as a template. This process is essential for maintaining chromosome integrity during cell division [67].

  5. Non-Homologous End Joining (NHEJ): This is a more error-prone repair pathway that directly ligates the ends of broken DNA without the need for a homologous template. NHEJ is crucial for repairing DSBs that occur throughout the cell cycle [68].

Recent studies have also revealed the intricate relationships between DNA repair mechanisms and other cellular processes, such as the immune response. For instance, DNA damage during inflammation can activate repair pathways that are essential for cell survival and effective immune responses [4]. Furthermore, the role of DNA repair in cancer biology has become increasingly apparent, with many therapeutic strategies focusing on targeting DNA repair pathways to enhance the efficacy of existing treatments. For example, inhibitors of Poly (ADP-ribose) polymerase (PARP) have been developed to exploit deficiencies in DNA repair pathways, particularly in tumors with BRCA mutations [68].

Additionally, research has uncovered novel functions of DNA repair proteins beyond their canonical roles in repairing DNA. These proteins are now recognized for their involvement in regulating gene expression and modulating cellular responses to stress, indicating a broader biological significance of DNA repair mechanisms [69].

In conclusion, the understanding of DNA repair mechanisms has significantly advanced, revealing a complex network of pathways that not only safeguard genomic integrity but also interact with various cellular processes. This knowledge is paving the way for innovative therapeutic approaches aimed at manipulating DNA repair pathways to improve cancer treatment outcomes and potentially address other diseases associated with DNA damage.

6.2 Gene Editing Technologies ​

DNA repair mechanisms are critical for maintaining genomic integrity and preventing the accumulation of mutations that can lead to various diseases, including cancer. The understanding of these mechanisms has advanced significantly, revealing a complex network of pathways that work to repair different types of DNA damage.

The primary DNA repair pathways include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double-strand break (DSB) repair, which can occur via homologous recombination (HR) or non-homologous end joining (NHEJ).

  1. Base Excision Repair (BER): This pathway is responsible for repairing small, non-helix-distorting base lesions that result from oxidative stress, alkylation, or deamination. The process involves the recognition and removal of damaged bases by specific DNA glycosylases, followed by the action of apurinic/apyrimidinic (AP) endonucleases that cleave the DNA backbone. The resulting single-strand break is then filled in by DNA polymerases and sealed by DNA ligases.

  2. Nucleotide Excision Repair (NER): NER is essential for repairing bulky DNA adducts and helix-distorting lesions, such as those caused by ultraviolet (UV) light. The process involves the recognition of the DNA damage, unwinding of the DNA around the lesion, excision of a short single-stranded DNA segment containing the damage, and resynthesis of the excised strand using the complementary strand as a template.

  3. Mismatch Repair (MMR): This pathway corrects errors that occur during DNA replication, such as base-base mismatches and insertion-deletion loops. MMR proteins recognize and bind to the mismatched base pair, excise the erroneous segment, and resynthesize the correct DNA sequence.

  4. Double-Strand Break Repair (DSB): DSBs can be repaired by two primary mechanisms:

    • Homologous Recombination (HR): This is an error-free repair process that utilizes a homologous template (usually the sister chromatid) to accurately repair the break. HR is particularly important during the S and G2 phases of the cell cycle when sister chromatids are available.
    • Non-Homologous End Joining (NHEJ): This is a quicker, but error-prone, repair mechanism that directly ligates the broken ends of DNA. NHEJ is active throughout the cell cycle and is crucial for repairing DSBs when a homologous template is not available.

In addition to these primary pathways, there are also specialized mechanisms such as translesion synthesis (TLS), which allows DNA polymerases to replicate past damaged sites, albeit with a higher risk of introducing mutations.

Recent research has also highlighted the interplay between DNA repair mechanisms and various biological processes, including aging and immune responses. For instance, DNA repair pathways are involved in the activation of immune responses to oxidative DNA damage, which is crucial for host-cell survival during inflammatory responses [4]. Furthermore, deficiencies in DNA repair processes are linked to various human diseases, including neurodegenerative disorders and cancer [3][70].

The complexity of DNA repair mechanisms and their regulation presents significant opportunities for therapeutic interventions, particularly in the context of cancer treatment. Modulating DNA repair pathways can enhance the efficacy of anticancer therapies by overcoming tumor resistance mechanisms [2]. Thus, ongoing research into the molecular details of DNA repair continues to provide insights that could lead to innovative strategies for treating diseases associated with DNA damage.

7 Conclusion ​

The study of DNA repair mechanisms has unveiled a complex interplay of pathways that are essential for maintaining genomic integrity and preventing diseases, particularly cancer. Major pathways such as base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double-strand break repair (DSBR) demonstrate the cell's capacity to rectify various forms of DNA damage. Current research highlights the critical roles these pathways play not only in cellular maintenance but also in aging, immune response, and the development of genetic disorders. Notably, deficiencies in DNA repair mechanisms can lead to increased mutation rates, genomic instability, and cancer susceptibility. The ongoing exploration of these mechanisms presents promising avenues for future research, particularly in the development of targeted therapies that exploit DNA repair deficiencies in cancer cells. As we advance our understanding of the molecular details governing DNA repair, we may uncover innovative strategies for enhancing therapeutic efficacy and improving patient outcomes in diseases associated with DNA damage.

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