Mismatch Repair vs. Nucleotide Excision Repair

Attribute	Mismatch Repair	Nucleotide Excision Repair
Definition	Corrects errors in DNA replication by removing and replacing mismatched nucleotides.	Repairs bulky DNA lesions caused by UV radiation and certain chemicals.
Types of DNA Damage	Mismatches, small insertions, and deletions.	Bulky DNA lesions, such as pyrimidine dimers and adducts.
Recognition Mechanism	Recognition of mismatched bases by MutS and MutL proteins.	Recognition of bulky DNA lesions by XPC protein complex.
Enzymes Involved	MutS, MutL, and MutH proteins.	XPC, XPA, XPF, and XPG proteins.
Repair Process	Removal of the mismatched nucleotide by exonuclease activity, followed by DNA resynthesis.	Excision of the damaged DNA strand, followed by DNA resynthesis.
Repair Efficiency	Highly efficient in correcting replication errors.	Relatively less efficient in repairing bulky DNA lesions.
Associated Diseases	Hereditary nonpolyposis colorectal cancer (HNPCC).	Xeroderma pigmentosum (XP).

Introduction

DNA repair mechanisms are crucial for maintaining the integrity of the genetic material in all living organisms. Two important repair pathways are Mismatch Repair (MMR) and Nucleotide Excision Repair (NER). While both pathways play essential roles in maintaining genomic stability, they differ in their mechanisms, target lesions, and associated proteins.

Mismatch Repair

Mismatch Repair (MMR) is a highly conserved pathway that corrects errors that occur during DNA replication, such as base-base mismatches and small insertion-deletion loops. These errors can lead to mutations and are a major source of genetic instability. MMR is initiated by the recognition of the mismatched base pairs by the MutS protein family, which includes MutSα and MutSβ in humans. Once the mismatch is recognized, the MutS protein recruits the MutL protein family, including MutLα and MutLβ, to form a complex that coordinates the subsequent repair steps.

The next step in MMR involves the excision of the incorrect nucleotide from the newly synthesized DNA strand. This is carried out by the exonuclease activity of the MutH protein, which creates a nick in the DNA strand near the mismatch. The exonuclease activity of the exonuclease 1 (Exo1) protein then removes the mismatched nucleotide, and DNA polymerase δ fills in the gap with the correct nucleotide. Finally, the DNA ligase I seals the nick, completing the repair process.

Nucleotide Excision Repair

Nucleotide Excision Repair (NER) is a versatile DNA repair pathway that removes a wide range of DNA lesions, including bulky adducts, UV-induced pyrimidine dimers, and certain types of chemical modifications. NER is initiated by the recognition of the lesion by the XPC-RAD23B complex in humans. This complex scans the DNA for distortions and structural abnormalities, marking the site of the lesion.

After lesion recognition, the transcription factor IIH (TFIIH) complex is recruited to the damaged site. TFIIH unwinds the DNA around the lesion, creating a bubble structure. The XPA protein then binds to the damaged DNA, followed by the recruitment of the endonucleases XPG and ERCC1-XPF. These endonucleases make incisions on both sides of the lesion, removing the damaged DNA fragment.

The gap left by the excised fragment is filled by DNA polymerase δ or ε, and the nick is sealed by DNA ligase I. In some cases, NER can also involve transcription-coupled repair (TC-NER), where the presence of RNA polymerase stalls at the lesion site, triggering a more rapid repair response.

Comparison of Mismatch Repair and Nucleotide Excision Repair

While both Mismatch Repair (MMR) and Nucleotide Excision Repair (NER) are essential DNA repair pathways, they differ in several aspects:

Target Lesions

MMR primarily targets base-base mismatches and small insertion-deletion loops that occur during DNA replication. These errors can arise due to misincorporation of nucleotides or slippage of the DNA polymerase. In contrast, NER is involved in the removal of a wide range of DNA lesions, including bulky adducts, UV-induced pyrimidine dimers, and chemical modifications. NER is particularly important for repairing DNA damage caused by environmental factors such as UV radiation and exposure to certain chemicals.

Recognition Mechanism

MMR relies on the recognition of mismatched base pairs by the MutS protein family, which initiates the repair process. MutS proteins scan the DNA for mismatches and recruit the MutL protein family to form a complex that coordinates the subsequent repair steps. In contrast, NER involves the recognition of DNA lesions by specific proteins such as XPC-RAD23B complex or the stalling of RNA polymerase during transcription-coupled repair. These recognition mechanisms allow NER to detect a wide range of DNA lesions.

Repair Steps

After recognition, MMR proceeds by excising the incorrect nucleotide from the newly synthesized DNA strand using the exonuclease activity of MutH and Exo1 proteins. The gap is then filled by DNA polymerase δ, and the nick is sealed by DNA ligase I. In NER, the damaged DNA fragment is excised by endonucleases such as XPG and ERCC1-XPF, leaving a gap that is filled by DNA polymerase δ or ε. Finally, DNA ligase I seals the nick, completing the repair process.

Associated Proteins

MMR involves the MutS and MutL protein families, including MutSα, MutSβ, MutLα, and MutLβ, which play crucial roles in recognizing and coordinating the repair of mismatches. In NER, proteins such as XPC-RAD23B, TFIIH, XPA, XPG, and ERCC1-XPF are involved in lesion recognition, DNA unwinding, incision, and repair. The specific proteins associated with each pathway highlight their distinct mechanisms and functions.

Importance in Genomic Stability

Both MMR and NER are vital for maintaining genomic stability. MMR prevents the accumulation of replication errors, reducing the risk of mutations and genetic instability. Defects in MMR can lead to a condition called Lynch syndrome, characterized by a high predisposition to certain types of cancer. On the other hand, NER plays a crucial role in repairing DNA damage caused by environmental factors, such as UV radiation. Defects in NER can result in disorders like xeroderma pigmentosum, which is associated with extreme sensitivity to sunlight and an increased risk of skin cancer.

Conclusion

Mismatch Repair (MMR) and Nucleotide Excision Repair (NER) are two important DNA repair pathways that play distinct roles in maintaining genomic stability. While MMR primarily corrects replication errors, NER is involved in the removal of a wide range of DNA lesions. The mechanisms, target lesions, repair steps, associated proteins, and importance in genomic stability differ between these pathways. Understanding the differences and similarities between MMR and NER is crucial for comprehending the intricate network of DNA repair mechanisms that safeguard the integrity of our genetic material.