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Publication Detail

Title: Structure and mechanism of pyrimidine-pyrimidone (6-4) photoproduct recognition by the Rad4/XPC nucleotide excision repair complex.

Authors: Paul, Debamita; Mu, Hong; Zhao, Hong; Ouerfelli, Ouathek; Jeffrey, Philip D; Broyde, Suse; Min, Jung-Hyun

Published In Nucleic Acids Res, (2019 07 09)

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.

PubMed ID: 31106376 Exiting the NIEHS site

MeSH Terms: DNA Repair; DNA-Binding Proteins/chemistry*; DNA-Binding Proteins/metabolism; DNA/chemistry*; Molecular Dynamics Simulation; Nucleic Acid Conformation; Protein Binding; Protein Domains; Pyrimidine Dimers/chemistry*; Pyrimidine Dimers/metabolism; Saccharomyces cerevisiae Proteins/chemistry*; Saccharomyces cerevisiae Proteins/metabolism

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