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Updated: Jan 29, 2026
The Number e as a Limit
Published on: January 12, 2026
Recognition of DNA damage by the Rad4 nucleotide excision repair protein
Jung-Hyun Min1, Nikola P Pavletich
1Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Abstract:
Mutations in the nucleotide excision repair (NER) pathway can cause the xeroderma pigmentosum skin cancer predisposition syndrome. NER lesions are limited to one DNA strand, but otherwise they are chemically and structurally diverse, being caused by a wide variety of genotoxic chemicals and ultraviolet radiation. The xeroderma pigmentosum C (XPC) protein has a central role in initiating global-genome NER by recognizing the lesion and recruiting downstream factors. Here we present the crystal structure of the yeast XPC orthologue Rad4 bound to DNA containing a cyclobutane pyrimidine dimer (CPD) lesion. The structure shows that Rad4 inserts a beta-hairpin through the DNA duplex, causing the two damaged base pairs to flip out of the double helix. The expelled nucleotides of the undamaged strand are recognized by Rad4, whereas the two CPD-linked nucleotides become disordered. These findings indicate that the lesions recognized by Rad4/XPC thermodynamically destabilize the Watson-Crick double helix in a manner that facilitates the flipping-out of two base pairs.
Insights
The xeroderma pigmentosum C (XPC) protein, Rad4, binds to damaged DNA by flipping out base pairs. This mechanism is crucial for initiating DNA repair pathways and preventing skin cancer.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Mutations in nucleotide excision repair (NER) cause xeroderma pigmentosum, a syndrome predisposing to skin cancer.
- The xeroderma pigmentosum C (XPC) protein initiates global-genome NER by recognizing DNA lesions.
- NER lesions are diverse, caused by UV radiation and genotoxic chemicals, and affect a single DNA strand.
Purpose of the Study:
- To elucidate the structural mechanism by which the XPC orthologue Rad4 recognizes DNA lesions.
- To understand how Rad4 binding initiates the NER pathway.
Main Methods:
- X-ray crystallography was used to determine the structure of yeast Rad4 bound to DNA containing a cyclobutane pyrimidine dimer (CPD) lesion.
Main Results:
- The crystal structure reveals Rad4 inserts a beta-hairpin into the DNA duplex, causing two base pairs to flip out.
- Rad4 recognizes nucleotides from the undamaged strand, while the CPD-damaged nucleotides become disordered.
- This interaction destabilizes the DNA double helix, facilitating lesion recognition.
Conclusions:
- The findings reveal a novel mechanism for DNA damage recognition by Rad4/XPC.
- This structural insight into lesion destabilization is key to understanding NER initiation.
- The study provides a foundation for further research into DNA repair and cancer predisposition.
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