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Structure and mechanism of pyrimidine–pyrimidone (6-4) photoproduct recognition by the Rad4/XPC nucleotide excision repair complex
- Source :
- Nucleic Acids Research
- Publication Year :
- 2019
- Publisher :
- Oxford University Press (OUP), 2019.
-
Abstract
- Failure in repairing ultraviolet radiation-induced DNA damage can lead to mutations and cancer. Among UV-lesions, the pyrimidine–pyrimidone (6-4) photoproduct (6-4PP) is removed from the genome much faster than the cyclobutane pyrimidine dimer (CPD), owing to the more efficient recognition of 6-4PP by XPC-RAD23B, a key initiator of global-genome nucleotide excision repair (NER). Here, we report a crystal structure of a Rad4–Rad23 (yeast XPC-Rad23B ortholog) bound to 6-4PP-containing DNA and 4-μs molecular dynamics (MD) simulations examining the initial binding of Rad4 to 6-4PP or CPD. This first structure of Rad4/XPC bound to a physiological substrate with matched DNA sequence shows that Rad4 flips out both 6-4PP-containing nucleotide pairs, forming an ‘open’ conformation. The MD trajectories detail how Rad4/XPC initiates ‘opening’ 6-4PP: Rad4 initially engages BHD2 to bend/untwist DNA from the minor groove, leading to unstacking and extrusion of the 6-4PP:AA nucleotide pairs towards the major groove. The 5′ partner adenine first flips out and is captured by a BHD2/3 groove, while the 3′ adenine extrudes episodically, facilitating ensuing insertion of the BHD3 β-hairpin to open DNA as in the crystal structure. However, CPD resists such Rad4-induced structural distortions. Untwisting/bending from the minor groove may be a common way to interrogate DNA in NER.
- Subjects :
- Saccharomyces cerevisiae Proteins
DNA Repair
Base pair
Stereochemistry
DNA damage
DNA repair
NAR Breakthrough Article
Pyrimidine dimer
Molecular Dynamics Simulation
Biology
03 medical and health sciences
chemistry.chemical_compound
Protein Domains
Genetics
Nucleotide
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
030302 biochemistry & molecular biology
Nucleotide-excision repair complex
DNA
3. Good health
DNA-Binding Proteins
chemistry
Pyrimidine Dimers
Nucleic Acid Conformation
Protein Binding
Nucleotide excision repair
Subjects
Details
- ISSN :
- 13624962 and 03051048
- Volume :
- 47
- Database :
- OpenAIRE
- Journal :
- Nucleic Acids Research
- Accession number :
- edsair.doi.dedup.....83cfaa3b0e255a77ddfe1e81e3498444