Nucleotide Excision Repair Mechanisms in Genetic Disorders

Nucleotide excision repair (NER) is a versatile DNA repair pathway responsible for detecting and excising a wide variety of bulky helix-distorting lesions, including ultraviolet (UV)-induced photoproducts and chemical adducts. NER operates through two subpathways: global genome NER, which surveys the entire genome for distortions, and transcription-coupled NER, which prioritises lesions that stall RNA polymerase II. Lesion recognition is mediated by damage sensors such as XPC and UV-DDB, followed by local DNA unwinding by the TFIIH helicase complex. Dual incision of the damaged strand is carried out by the XPF-ERCC1 and XPG endonucleases, after which DNA synthesis and ligation restore genome integrity. Defects in NER components give rise to a spectrum of inherited disorders, most notably xeroderma pigmentosum (XP), characterised by extreme UV sensitivity and elevated skin cancer risk, and Cockayne syndrome (CS), in which neurodevelopmental abnormalities occur with little tumour predisposition. Recent advances have elucidated structural features of core NER proteins, uncovered non-canonical roles of NER factors in genome maintenance, and revealed links between repair deficiency and processes such as ribosome biogenesis. These insights are informing improved diagnostic tools, genotype–phenotype correlations and potential therapeutic strategies, including small-molecule modulators of NER activity and gene-editing approaches to correct pathogenic variants.

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Nucleotide Excision Repair Mechanisms in Genetic Disorders publication trend

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

Technical terms

Nucleotide excision repair (NER): A DNA repair pathway that recognises and removes bulky helix-distorting lesions through dual incision and gap-filling synthesis.

Endonuclease: An enzyme that cleaves the phosphodiester backbone of DNA at internal sites, critical for excising damaged nucleotides in NER.

R-loop: A three-strand nucleic acid structure comprising an RNA–DNA hybrid and displaced single-stranded DNA, which can impede replication and transcription if unresolved.

Ribosome biogenesis: The multistep cellular process of synthesising and assembling ribosomal RNA and proteins to form functional ribosomes, essential for protein production.

Transcription-coupled NER: A subpathway of NER that specifically targets lesions blocking RNA polymerase II, thereby prioritising repair on actively transcribed genes.

References

1. XPG: a multitasking genome caretaker. Cellular and Molecular Life Sciences (2022).
2. Identification of a ERCC5 c.2333T>C (L778P) Variant in Two Tunisian Siblings With Mild Xeroderma Pigmentosum Phenotype. Frontiers in Genetics (2019).
3. A stable XPG protein is required for proper ribosome biogenesis: Insights on the phenotype of combinate Xeroderma Pigmentosum/Cockayne Syndrome patients. PLOS ONE (2022).