Kinetic gating mechanism of DNA damage recognition by Rad4/XPC.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 25562780.
- Also identified by DOI 10.1038/ncomms6849 and PMC identifier 4354021.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The xeroderma pigmentosum C (XPC) complex initiates nucleotide excision repair by recognizing DNA lesions before recruiting downstream factors. How XPC detects structurally diverse lesions embedded within normal DNA is unknown. Here we present a crystal structure that captures the yeast XPC orthologue (Rad4) on a single register of undamaged DNA. The structure shows that a disulphide-tethered Rad4 flips out normal nucleotides and adopts a conformation similar to that seen with damaged DNA. Contrary to many DNA repair enzymes that can directly reject non-target sites as structural misfits, our results suggest that Rad4/XPC uses a kinetic gating mechanism whereby lesion selectivity arises from the kinetic competition between DNA opening and the residence time of Rad4/XPC per site. This mechanism is further supported by measurements of Rad4-induced lesion-opening times using temperature-jump perturbation spectroscopy. Kinetic gating may be a general mechanism used by site-specific DNA-binding proteins to minimize time-consuming interrogations of non-target sites.
Medical subject headings
- DNA
- DNA Damage
- DNA Repair
- DNA-Binding Proteins
- Models, Molecular
- Multiprotein Complexes
- Saccharomyces cerevisiae
- Saccharomyces cerevisiae Proteins