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Related Concept Videos

Nucleotide Excision Repair01:08

Nucleotide Excision Repair

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Overview
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Nucleotide Excision Repair01:38

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DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
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The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
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DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
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One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
The first step of...
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Updated: Jan 16, 2026

Atomic Force Microscopy Investigations of DNA Lesion Recognition in Nucleotide Excision Repair
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Minimum Energy Pathway for Lesion Recognition and DNA Binding by RAD4/XPC.

Aadarsh Raghunathan1, Marimuthu Krishnan1

  • 1Center for Computational Natural Sciences and Bioinformatics (CCNSB), International Institute of Information Technology, Gachibowli, Hyderabad, Telangana 500032, India.

Journal of Chemical Information and Modeling
|September 25, 2025
PubMed
Summary

The XPC/RAD4 protein initiates DNA repair by recognizing UV-damaged DNA. Molecular dynamics reveal a rate-limiting DNA distortion and base-flipping mechanism crucial for lesion repair.

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Area of Science:

  • Molecular Biology
  • Biochemistry
  • Genetics

Background:

  • UV radiation causes DNA damage, forming pyrimidine-pyrimidone (6-4) photoproducts (6-4PP).
  • The XPC/RAD4 protein complex is essential for detecting 6-4PP and initiating nucleotide excision repair.
  • Understanding the precise mechanism of XPC/RAD4-mediated lesion recognition and repair is critical for genomic integrity.

Purpose of the Study:

  • To elucidate the molecular mechanism by which XPC/RAD4 initiates repair of UV-induced DNA lesions.
  • To map the energy landscape and conformational changes involved in XPC/RAD4 binding to damaged DNA.

Main Methods:

  • Molecular dynamics (MD) simulations
  • Umbrella sampling
  • Nudged elastic band (NEB) method to determine the minimum energy path (MEP).

Main Results:

  • The initial DNA interrogation involves partial unwinding and opening, with partial lesion extrusion.
  • A rate-limiting step, characterized by 5' base flipping, was identified as a bottleneck.
  • Sequential base flipping (lesion, 5' base, 3' bases) and β-hairpin insertion stabilize the final XPC/RAD4-DNA complex.

Conclusions:

  • The study reveals key conformational intermediates and energetics governing XPC/RAD4's DNA repair initiation.
  • Insights into the base-flipping mechanism provide a deeper understanding of nucleotide excision repair.
  • This work advances knowledge of DNA damage response pathways relevant to skin disorders and cancer.