Nucleotide Excision Repair, Xeroderma Pigmentosum and Platinum Response

Two Ways In: Global and Transcription-Coupled

Global genome nucleotide excision repair surveys the entire genome for helix-distorting lesions. Transcription-coupled repair is triggered when RNA polymerase stalls at a lesion in an actively transcribed gene, prioritising repair of the template strand.

After recognition, the DNA around the lesion is unwound, a short single-stranded segment of about 25 to 30 nucleotides containing the damage is excised by the ERCC1-XPF and XPG nucleases, and a polymerase and ligase restore the sequence.

Xeroderma Pigmentosum

Biallelic loss of function in nucleotide-excision-repair genes (the XP complementation groups) causes xeroderma pigmentosum, characterised by extreme sun sensitivity and a greatly increased risk of skin cancers at an early age, sometimes with neurological features.

The condition demonstrates the pathway's role in protecting against ultraviolet mutagenesis. Tumours from affected individuals carry a heavy load of the C>T changes at dipyrimidine sites that define the ultraviolet mutational signature.

The ERCC1 Biomarker Problem

Because nucleotide excision repair removes platinum-DNA adducts, low pathway activity should in principle predict greater platinum sensitivity. Many studies correlated low ERCC1 expression with better platinum response in lung, ovarian and other cancers.

Translation to a validated clinical test has not succeeded, partly because available antibodies do not reliably distinguish the functional ERCC1 isoform and because expression is only an indirect readout of repair capacity. A pathway concept that is biologically sound is not automatically a usable biomarker.

What It Means in Practice Today

Despite decades of study, nucleotide-excision-repair status does not currently guide platinum dosing or drug choice in routine oncology. The clearest practical use of the pathway is recognising xeroderma pigmentosum, where a diagnosis drives rigorous ultraviolet protection, dermatological surveillance and avoidance of unnecessary radiation.

In tumour genomics, a strong ultraviolet or platinum-adduct mutational signature can support a suspected exposure history or a repair defect, but this is interpretive context rather than an actionable result. Research interest has moved toward combining repair-pathway readouts with other markers rather than relying on ERCC1 alone.

Key Takeaways

• ·Nucleotide excision repair removes bulky, helix-distorting lesions including UV photoproducts and platinum adducts.
• ·Inherited loss causes xeroderma pigmentosum, with early skin cancers and a strong UV mutational signature.
• ·Low ERCC1 has been linked to platinum sensitivity in research but is not an established clinical biomarker.