Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.


The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Your Environment. Your Health.

Publication Detail

Title: The DNA damage-sensing NER repair factor XPC-RAD23B does not recognize bulky DNA lesions with a missing nucleotide opposite the lesion.

Authors: Feher, Katie M; Kolbanovskiy, Alexander; Durandin, Alexander; Shim, Yoonjung; Min, Jung-Hyun; Lee, Yuan Cho; Shafirovich, Vladimir; Mu, Hong; Broyde, Suse; Geacintov, Nicholas E

Published In DNA Repair (Amst), (2020 12)

Abstract: The Nucleotide Excision Repair (NER) mechanism removes a wide spectrum of structurally different lesions that critically depend on the binding of the DNA damage sensing NER factor XPC-RAD23B (XPC) to the lesions. The bulky mutagenic benzo[a]pyrene diol epoxide metabolite-derived cis- and trans-B[a]P-dG lesions (G*) adopt base-displaced intercalative (cis) or minor groove (trans) conformations in fully paired DNA duplexes with the canonical C opposite G* (G*:C duplexes). While XPC has a high affinity for binding to these DNA lesions in fully complementary double-stranded DNA, we show here that deleting only the C in the complementary strand opposite the lesion G* embedded in 50-mer duplexes, fully abrogates XPC binding. Accurate values of XPC dissociation constants (KD) were determined by employing an excess of unmodified DNA as a competitor; this approach eliminated the binding and accumulation of multiple XPC molecules to the same DNA duplexes, a phenomenon that prevented the accurate estimation of XPC binding affinities in previous studies. Surprisingly, a detailed comparison of XPC dissociation constants KD of unmodified and lesion-containing G*:Del complexes, showed that the KD values were -2.5-3.6 times greater in the case of G*:Del than in the unmodified G:Del and fully base-paired G:C duplexes. The origins of this unexpected XPC lesion avoidance effect is attributed to the intercalation of the bulky, planar B[a]P aromatic ring system between adjacent DNA bases that thermodynamically stabilize the G*:Del duplexes. The strong lesion-base stacking interactions associated with the absence of the partner base, prevent the DNA structural distortions needed for the binding of the BHD2 and BHD3 β-hairpins of XPC to the deletion duplexes, thus accounting for the loss of XPC binding and the known NER-resistance of G*:Del duplexes.

PubMed ID: 33035795 Exiting the NIEHS site

MeSH Terms: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide/chemistry; 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide/metabolism*; DNA Adducts/chemistry; DNA Adducts/metabolism*; DNA Repair Enzymes/metabolism; DNA Repair*; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/metabolism*; DNA/chemistry; DNA/metabolism; Humans; Kinetics; Molecular Dynamics Simulation; Nucleic Acid Conformation; Protein Conformation; Saccharomyces cerevisiae Proteins/chemistry; Saccharomyces cerevisiae Proteins/metabolism*; Saccharomyces cerevisiae/enzymology; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae/metabolism; Substrate Specificity

to Top