DNA Repair Disorders in Xeroderma Pigmentosum

Xeroderma pigmentosum is a rare autosomal recessive disorder arising from inherited defects in DNA repair pathways responsible for removing ultraviolet-induced lesions. Mutations in any of eight complementation groups—seven genes operating in nucleotide excision repair or the DNA polymerase η gene involved in translesion synthesis—result in hypersensitivity to ultraviolet radiation, early-onset lentiginosis, and a dramatically elevated risk of cutaneous malignancy. Beyond dermatological manifestations, subsets of patients experience progressive neurological degeneration, sensorineural deficits and an emerging predisposition to internal tumours. The clinical severity varies with genotype, mutation type and residual repair capacity, while profound heterogeneity in mutational profiles influences cancer risk and therapeutic response. Rigorous photoprotection remains the cornerstone of management, yet advances in molecular diagnostics, genotype–phenotype correlation and targeted interventions are reshaping prognosis and care pathways worldwide.

Research from Nature Portfolio

Recent studies have illuminated how differential nucleotide excision repair activity shapes the mutational landscape of skin cancers in xeroderma pigmentosum. Whole-genome analyses of tumours across distinct complementation groups reveal transcription-coupled repair extending into intergenic regions and clarify polymerase η’s role in error-free bypass of bulky photolesions. Complementary genomic profiling of internal gynae-oncological tumours in XP-C patients has identified a high burden of single-base substitutions with a signature indicative of repair deficiency, prompting development of tailored treatment regimens that circumvent conventional DNA-damaging chemotherapy and emphasise genotype-guided therapeutic decisions.

DNA Repair Disorders in Xeroderma Pigmentosum publication trend

The graph below shows the total number of articles in dna repair disorders in xeroderma pigmentosum across all publications each year (not limited to Nature Index journals).

Technical terms

Nucleotide excision repair (NER): A DNA repair mechanism that recognises and excises helix-distorting lesions, such as UV-induced photoproducts, followed by replacement of the excised strand.

Translesion synthesis (TLS): A replication process that employs specialised DNA polymerases to bypass lesions that would otherwise stall conventional polymerases.

Complementation group: A classification of xeroderma pigmentosum patients based on the specific gene mutated, which determines the deficient repair pathway component.

Mutational signature: A characteristic pattern of base substitutions and indels in the genome that reflects underlying DNA damage and repair processes.

Antisense oligonucleotide: A short, synthetic nucleic acid designed to bind pre-mRNA and modulate splicing or expression of target genes.

References

1. Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients. Nature Communications (2023).
2. Neurological disease in xeroderma pigmentosum: prospective cohort study of its features and progression. Brain (2023).
3. Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum. Proceedings of the National Academy of Sciences of the United States of America (2023).
4. Early-onset gynecological tumors in DNA repair-deficient xeroderma pigmentosum group C patients: a case series. Communications Medicine (2023).
5. The French Cohort of DNA Repair-Deficient Xeroderma Pigmentosum Patients: Risk of Hematological Malignancies. Cancers (2023).