[No authors listed]
The interplay between nucleotide excision repair (NER) and base excision repair (BER) of nonbulky, oxidatively generated DNA lesions has long been a subject of significant interest. The hydantoin oxidation products of 8-oxoguanine, spiroiminodihydantoin (Sp) and 5-guanidinohydantoin (Gh), are substrates of both BER and NER in HeLa cell extracts and human cells [Shafirovich, V., et al. (2019) Chem. Res. Toxicol. 32, 753-761]. The primary factor that recognizes DNA lesions is the DNA damage-sensing factor XPC-RAD23B (XPC), while the glycosylase NEIL1 is known to remove Gh and Sp lesions from double-stranded DNA. It is shown here that in aqueous solutions containing nanomolar concentrations of proteins, XPC and NEIL1 compete for binding to 147-mer oligonucleotide duplexes that contain single Gh or Sp lesions under conditions of [protein] ⫠[DNA], thus inhibiting the rate of BER catalyzed by NEIL1. The non-covalently bound NEIL1 molecules can be displaced by XPC at concentration ratios R = [XPC]/[NEIL1] > 0.2, while full displacement of NEIL1 is observed at R ⥠0.5. In the absence of XPC and under single-turnover conditions, only the burst phase is observable. However, with a progressive increase in the XPC concentration, the amplitude of the burst phase decreases gradually, and a slower time-dependent phase of incision product formation manifests itself with rate constants of 3.0 à 10-3 s-1 (Gh) and 0.90 à 10-3 s-1 (Sp). These slow kinetics are attributed to the dissociation of XPC-DNA complexes that allow for the rebinding of NEIL1 to the temporarily exposed Gh or Sp lesions, and the incisions observed under these steady-state conditions.
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