Nucleotide Excision Repair Mechanisms in DNA Damage Response Across Organisms

Nucleotide excision repair (NER) is a highly conserved pathway that recognises and removes bulky lesions and helix‐distorting adducts from DNA, thereby safeguarding genomic integrity. In bacteria, the UvrABC complex orchestrates damage recognition, dual incision and excision of a short oligonucleotide, followed by gap filling and ligation. In archaea and eukaryotes, an analogous set of factors—primarily the XPC complex for global surveillance and RNA polymerase‐associated machinery for transcription‐coupled repair—initiates lesion detection. A central hub of eukaryotic NER is the multisubunit TFIIH complex, whose helicase and ATPase activities unwind DNA around the lesion to allow sequential incisions by structure‐specific endonucleases (XPF–ERCC1 and XPG). Following excision, repair synthesis and ligation restore the original sequence. Across kingdoms, NER balances versatility and specificity: prokaryotic systems rely on direct recognition of DNA distortions, whereas eukaryotes integrate chromatin context, histone modifications and transcriptional status to prioritise repair. Inter‐organismal comparisons have revealed common mechanistic themes—damage verification by helicases, protein modifications governing factor exchange and coordination with transcription and replication. The global significance of NER extends from preventing UV‐induced skin cancers to countering environmental carcinogens and mediating responses to chemotherapeutic agents. Comparative studies illuminate evolutionary adaptations of NER subpathways, uncovering how differential protein architectures and regulatory networks optimise repair efficiency under diverse cellular and genomic landscapes.

Research from Nature Portfolio

Recent structural work has captured an NER intermediate in which the XPD helicase subunit of TFIIH actively separates duplex DNA and stalls at a model interstrand cross‐link. High‐resolution cryo-EM reveals unexpected involvement of the Arch domain in DNA strand separation and identifies discrete surface regions essential for helicase function and damage verification. Mutational and biochemical analyses further demonstrate that these regions also modulate core TFIIH translocase activity, shedding new light on how damage verification and bubble formation are coupled during excision.

High-resolution mapping of UV‐induced cyclobutane pyrimidine dimers (CPDs) in human melanocytes has uncovered the role of ETS family transcription factors in shaping mutation landscapes. A novel capture‐sequencing approach shows that specific ETS binding sites form CPD hotspots upon UV exposure, accounting for recurrent driver and passenger mutations in melanoma genomes. This work provides a mechanistic basis for how sequence context and protein–DNA interactions influence lesion formation and mutagenesis in a chromatin environment.

Nucleotide Excision Repair Mechanisms in DNA Damage Response Across Organisms publication trend

The graph below shows the total number of articles in nucleotide excision repair mechanisms in dna damage response across organisms across all publications each year (not limited to Nature Index journals).

Technical terms

Nucleotide Excision Repair (NER): A DNA repair pathway that removes bulky, helix-distorting lesions via dual incision, excision of an oligonucleotide and subsequent gap-filling synthesis.

Global Genomic Repair (GGR): The subpathway of NER that surveys the entire genome for distortions, primarily initiated by the XPC recognition complex.

Transcription-Coupled Repair (TCR): A specialised NER subpathway triggered by RNA polymerase stalling at lesions, prioritising repair of transcribed strands.

TFIIH: A multiprotein complex with helicase/ATPase activities that opens DNA around lesions and plays dual roles in transcription initiation and NER.

Cyclobutane Pyrimidine Dimer (CPD): A UV-induced lesion formed by covalent bonding between adjacent pyrimidine bases, distorting DNA and impeding replication.

DNA adduct: A covalent modification of DNA bases by physical or chemical agents that can disrupt base pairing and block transcription or replication.

References

1. XPD stalled on cross-linked DNA provides insight into damage verification. Nature Structural & Molecular Biology (2024).
2. Detecting recurrent passenger mutations in melanoma by targeted UV damage sequencing. Nature Communications (2023).
3. Nucleotide excision repair of aflatoxin-induced DNA damage within the 3D human genome organization. Nucleic Acids Research (2024).
4. Quantification and Mapping of Alkylation in the Human Genome Reveal Single Nucleotide Resolution Precursors of Mutational Signatures. ACS Central Science (2023).