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Nucleotide Excision Repair Mechanism: Molecular Players and Pathways

Overview of Nucleotide Excision Repair Mechanism: Molecular Players and Pathways

Nucleotide excision repair (NER) is a crucial mechanism that cells use to repair DNA damage caused by various factors, including exposure to ultraviolet (UV) radiation and certain chemicals. This repair mechanism is highly conserved across species, from bacteria to humans, highlighting its importance in maintaining genomic stability.

The NER mechanism involves a series of coordinated steps that are carried out by a complex network of molecular players. The first step in NER is the recognition of DNA damage. This is achieved by a group of proteins known as damage recognition factors, which scan the DNA for abnormalities. These factors have the ability to detect a wide range of DNA lesions, including bulky adducts and distortions in the DNA helix.

Once the damage is recognized, the next step is the recruitment of additional proteins to form a pre-incision complex. This complex includes several proteins, such as XPC, XPA, and RPA, which work together to stabilize the damaged DNA and prepare it for excision. XPC plays a crucial role in the initial recognition of the damage, while XPA and RPA help to unwind the DNA and protect it from further damage.

After the formation of the pre-incision complex, the damaged DNA is incised on both sides of the lesion by a structure-specific endonuclease called XPG. This incision creates a small DNA fragment containing the damaged nucleotide, which is then removed by the action of another endonuclease called XPF-ERCC1. This excision step is followed by the synthesis of a new DNA strand to replace the removed fragment.

The synthesis of the new DNA strand is carried out by DNA polymerases, which are enzymes responsible for copying the DNA sequence. In NER, a specialized DNA polymerase called polη is recruited to the site of the lesion. Polη has the unique ability to bypass certain types of DNA damage, such as UV-induced thymine dimers, allowing for the accurate replication of the damaged DNA.

Once the new DNA strand is synthesized, the final step in NER is the ligation of the DNA ends. This is achieved by a protein complex called DNA ligase, which seals the nick in the DNA backbone, completing the repair process.

In addition to the core NER pathway described above, there are also alternative pathways that can be activated under certain conditions. These pathways involve different sets of molecular players and are thought to play a role in repairing specific types of DNA damage. For example, the transcription-coupled repair (TCR) pathway is activated when DNA damage occurs in actively transcribed regions of the genome. This pathway relies on the recruitment of additional proteins, such as CSA and CSB, to facilitate the repair process.

In conclusion, the nucleotide excision repair mechanism is a complex and highly regulated process that cells use to repair DNA damage. It involves a series of coordinated steps carried out by a network of molecular players. Understanding the molecular players and pathways involved in NER is crucial for unraveling the mechanisms underlying DNA repair and maintaining genomic stability.

Role of DNA Damage Recognition Proteins in Nucleotide Excision Repair Mechanism

Nucleotide Excision Repair Mechanism: Molecular Players and Pathways

The nucleotide excision repair (NER) mechanism is a crucial process that helps maintain the integrity of our DNA. It is responsible for repairing a wide range of DNA lesions, including those caused by exposure to ultraviolet (UV) radiation and certain chemicals. Understanding the molecular players and pathways involved in NER is essential for comprehending the intricate nature of this repair mechanism.

One of the key steps in NER is the recognition of DNA damage. This is where DNA damage recognition proteins come into play. These proteins have the ability to identify and bind to various types of DNA lesions. One such protein is XPC, which acts as a sensor for a wide range of DNA damage, including UV-induced lesions and bulky chemical adducts.

Once the DNA damage is recognized, the next step in NER is the recruitment of other proteins to the site of damage. This recruitment is facilitated by the interaction between the DNA damage recognition proteins and other proteins involved in the repair process. For example, XPC interacts with the protein complex known as TFIIH, which is essential for the subsequent steps of NER.

TFIIH is a multi-subunit complex that plays a crucial role in NER. It not only helps recruit other proteins to the site of damage but also has helicase activity, which is necessary for unwinding the DNA around the lesion. This unwinding allows for the excision of the damaged DNA strand.

Another important protein involved in NER is XPA. XPA interacts with both XPC and TFIIH and plays a critical role in stabilizing the protein complex at the site of damage. It also helps in verifying the presence of DNA lesions and assists in the recruitment of other repair proteins.

Once the damaged DNA strand is unwound, the next step in NER is the excision of the lesion. This is carried out by a set of endonucleases, including XPG and XPF-ERCC1. These endonucleases make incisions on either side of the lesion, resulting in the removal of the damaged DNA fragment.

After the excision of the damaged DNA strand, the gap is filled by DNA synthesis. This process is mediated by DNA polymerases, such as DNA polymerase δ and DNA polymerase ε. These polymerases synthesize a new DNA strand using the intact complementary strand as a template.

Finally, the newly synthesized DNA strand is ligated to the original DNA strand by DNA ligase. This completes the repair process and restores the integrity of the DNA.

In conclusion, the role of DNA damage recognition proteins in the nucleotide excision repair mechanism is crucial for the efficient and accurate repair of DNA lesions. Proteins like XPC, TFIIH, XPA, and various endonucleases and polymerases work together in a coordinated manner to recognize, excise, and repair damaged DNA. Understanding the molecular players and pathways involved in NER not only provides insights into the fundamental mechanisms of DNA repair but also has implications for the development of therapeutic strategies targeting DNA damage and repair processes.

Significance of Transcription-Coupled Nucleotide Excision Repair in Genome Stability

Nucleotide Excision Repair Mechanism: Molecular Players and Pathways

The maintenance of genome stability is crucial for the proper functioning of cells and the prevention of diseases such as cancer. One of the mechanisms that cells employ to repair damaged DNA is nucleotide excision repair (NER). NER is a highly conserved process that removes a wide range of DNA lesions, including those induced by ultraviolet (UV) radiation and chemical agents.

NER can be divided into two subpathways: global genome repair (GGR) and transcription-coupled repair (TCR). While GGR operates throughout the genome, TCR specifically targets lesions that block the progression of RNA polymerase during transcription. This article will focus on the significance of TCR in maintaining genome stability.

Transcription is a fundamental process in cells that involves the synthesis of RNA molecules from DNA templates. It is essential for gene expression and the production of proteins. However, the elongation of RNA polymerase can be hindered by DNA lesions, leading to stalling of the transcription machinery. This stalling can have severe consequences for cells, as it can result in the formation of DNA breaks and the collapse of replication forks.

To prevent these detrimental effects, cells have evolved TCR as a specialized repair pathway. TCR is initiated by the recognition of the stalled RNA polymerase by the Cockayne syndrome group B (CSB) protein. CSB acts as a sensor for transcription-blocking lesions and recruits other NER factors to the site of damage. These factors include the xeroderma pigmentosum group A (XPA) protein, which is involved in DNA unwinding, and the xeroderma pigmentosum group G (XPG) protein, which cleaves the damaged DNA strand.

Once the NER factors are assembled at the site of damage, the damaged DNA strand is excised by the action of the excision repair cross-complementation group 1 (ERCC1) and xeroderma pigmentosum group F (XPF) endonucleases. This excision creates a gap in the DNA, which is then filled by DNA synthesis and ligation.

The significance of TCR in maintaining genome stability becomes evident when considering the consequences of its dysfunction. Mutations in the genes encoding TCR factors, such as CSB, result in Cockayne syndrome, a rare genetic disorder characterized by premature aging and neurological abnormalities. These individuals are highly sensitive to UV radiation and have an increased risk of developing cancer.

Furthermore, recent studies have shown that TCR is not only involved in the repair of transcription-blocking lesions but also in the resolution of DNA-RNA hybrids, known as R-loops. R-loops can form during transcription and can be a source of genomic instability. TCR factors, including CSB and XPG, have been found to play a role in preventing R-loop accumulation and resolving these structures.

In conclusion, TCR is a specialized repair pathway that plays a crucial role in maintaining genome stability. By targeting transcription-blocking lesions and resolving DNA-RNA hybrids, TCR prevents the detrimental effects of stalled transcription on DNA integrity. Understanding the molecular players and pathways involved in TCR not only provides insights into the fundamental processes of DNA repair but also has implications for the development of therapeutic strategies for diseases associated with genome instability.

Conclusion

In conclusion, the nucleotide excision repair (NER) mechanism is a crucial DNA repair pathway that helps maintain genomic integrity. It involves several molecular players, including the XPC complex, TFIIH complex, XPA, XPG, and XPF-ERCC1, which work together to identify and remove DNA lesions. The NER pathway consists of two sub-pathways, global genome repair (GGR) and transcription-coupled repair (TCR), which differ in their recognition of DNA damage. Understanding the molecular players and pathways involved in NER is essential for comprehending the mechanisms underlying DNA repair and its implications in maintaining genome stability.

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