Nucleotide Excision Repair Vs Mismatch Repair

Nucleotide Excision Repair vs. Mismatch Repair: A Deep Dive into DNA Damage Control

Maintaining the integrity of our genetic material is paramount for cellular survival and organismal health. DNA, the blueprint of life, is constantly under assault from both endogenous and exogenous sources, leading to a variety of DNA lesions. These lesions, if left unrepaired, can lead to mutations, genomic instability, and ultimately, disease, including cancer. Our cells have evolved sophisticated mechanisms to combat this threat, and among the most prominent are nucleotide excision repair (NER) and mismatch repair (MMR). While both are crucial for maintaining genome stability, they target distinct types of DNA damage and employ different repair strategies. This article will delve into the intricacies of NER and MMR, highlighting their mechanisms, substrates, and the consequences of their dysfunction.

Nucleotide Excision Repair (NER): The Swiss Army Knife of DNA Repair

NER is a highly versatile DNA repair pathway capable of removing a wide range of bulky DNA lesions that distort the DNA helix. These lesions can arise from various sources, including:

• UV radiation: UV light induces the formation of pyrimidine dimers (cyclobutane pyrimidine dimers or CPDs and pyrimidine(6-4)pyrimidone photoproducts or 6-4PPs), which are the most common NER substrates.
• Chemical carcinogens: Many chemical compounds, such as polycyclic aromatic hydrocarbons (PAHs) and aflatoxins, form bulky adducts with DNA bases, distorting the DNA helix and hindering replication and transcription.
• Oxidative stress: Reactive oxygen species (ROS) can cause a variety of DNA modifications, some of which are large enough to be recognized and repaired by NER.

NER operates through a multi-step process involving several key proteins:

The NER Mechanism: A Detailed Look

1. Damage Recognition: The initial step involves recognizing the DNA damage. This is accomplished by different mechanisms depending on the type of lesion and the specific NER sub-pathway:

   • Global Genome NER (GG-NER): This pathway operates throughout the genome and relies on damage recognition proteins such as XPC in humans (Rad4 in yeast) and its associated factor, hHR23B. These proteins scan the DNA for distortions in the helix, irrespective of transcription status.

   • Transcription-Coupled NER (TC-NER): This pathway specifically targets lesions that block RNA polymerase II transcription. The stalled polymerase serves as a signal for recruitment of NER factors, including CSA and CSB proteins. TC-NER ensures the repair of lesions that directly affect gene expression.

2. DNA unwinding and incision: Once the damage is recognized, a complex of proteins unwinds the DNA around the lesion. This involves the recruitment of the TFIIH complex, which possesses both helicase and kinase activities. Two incisions are then made, one on the 5' side and one on the 3' side of the lesion, by endonucleases XPF/ERCC1 and XPG, respectively.

3. Excision: The damaged oligonucleotide, typically 25-30 nucleotides long, is excised from the DNA strand.

4. DNA synthesis: DNA polymerase fills the gap created by the excision using the undamaged strand as a template.

5. Ligation: DNA ligase seals the nick, completing the repair process.

Consequences of NER Deficiency

Defects in NER genes lead to a variety of human diseases, most notably:

• Xeroderma pigmentosum (XP): This rare genetic disorder is characterized by extreme sun sensitivity, premature aging, and a dramatically increased risk of skin cancer. XP is caused by mutations in any of the genes involved in NER.

• Cockayne syndrome (CS): This syndrome is characterized by developmental defects, neurological problems, and premature aging. It is caused by mutations in the CS genes, which are involved in TC-NER.

• Trichothiodystrophy (TTD): This disorder presents with brittle hair, intellectual disability, and other developmental abnormalities. It often involves mutations in genes involved in transcription or DNA repair.

Mismatch Repair (MMR): Maintaining Fidelity During Replication

Mismatch repair (MMR) is a highly conserved pathway dedicated to correcting errors that occur during DNA replication. These errors can include:

• Base-base mispairs: Incorrect pairing of nucleotides, such as A-C or G-T.
• Small insertion/deletion loops (IDLs): Addition or removal of one or a few nucleotides during replication.

MMR is crucial for maintaining genomic stability and preventing mutations that could lead to cancer. Its accuracy is essential, as errors introduced by MMR itself could lead to further problems.

The MMR Mechanism: Accuracy is Key

1. Mismatch Recognition: The mismatch is recognized by a complex of proteins, including MutSα (MSH2-MSH6) in humans, which binds to the mismatch and initiates the repair process. MutSβ (MSH2-MSH3) recognizes insertion/deletion loops.

2. Strand Discrimination: A critical step in MMR is the identification of the newly synthesized strand, which contains the error. This is achieved through the recognition of nicks or gaps in the lagging strand, which are present immediately after replication. In eukaryotes, the mechanism of strand discrimination is still under investigation but involves PCNA and other factors.

3. Excision: The newly synthesized strand is nicked near the mismatch by endonuclease activities. A section of DNA encompassing the mismatch is then excised by an exonuclease.

4. Resynthesis and Ligation: The gap is filled by DNA polymerase, and the nick is sealed by DNA ligase, restoring the correct DNA sequence.

Consequences of MMR Deficiency

Defects in MMR genes are strongly associated with hereditary nonpolyposis colorectal cancer (Lynch syndrome) and other cancers. The inability to correct replication errors leads to an accumulation of mutations, increasing the risk of developing tumors.

NER vs. MMR: A Comparison

The Interplay Between NER and MMR: A Complex Network

While NER and MMR address distinct types of DNA damage, they can interact and influence each other. For example, the presence of a mismatch can affect the efficiency of NER, and vice versa. Moreover, both pathways are part of a larger network of DNA repair pathways that work together to maintain genome stability. The cell’s response to DNA damage is highly coordinated, with different pathways being activated depending on the nature and extent of the damage.

Conclusion: Guardians of the Genome

Nucleotide excision repair and mismatch repair are essential DNA repair pathways that safeguard the integrity of our genome. Their distinct mechanisms and substrates highlight the cellular sophistication in combating DNA damage. Defects in these pathways can lead to severe human diseases, particularly cancer, underlining their critical role in preventing genomic instability and maintaining cellular health. Further research into these complex repair pathways continues to provide crucial insights into the mechanisms of disease and the development of novel therapeutic strategies. Understanding the intricate interplay between NER, MMR, and other DNA repair pathways is key to advancing our knowledge of genomic stability and its impact on human health. Future research may reveal further interactions and synergistic effects between these pathways, providing additional targets for therapeutic interventions in cancer and other genetic disorders. The constant battle between DNA damage and repair mechanisms is a testament to the dynamic and crucial role of DNA repair in sustaining life.