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Studies on in vitro modulatory effects to base excision repair enzymes induced by small molecule binding to

Anisa Ulhusna1, Asako Murata2, Kazuhiko Nakatani1

  • 1Department of Regulatory Bioorganic Chemistry, SANKEN (The Institute of Scientific and Industrial Research), Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan.

Bioorganic & Medicinal Chemistry Letters
|February 21, 2025
PubMed

Insights

This study shows naphthyridine azaquinolone (NA) binds to damaged DNA repeats. This binding partially inhibits the Base Excision Repair (BER) pathway, potentially reducing repeat instability.

Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Chemical Biology

Background:

  • The Base Excision Repair (BER) pathway is crucial for maintaining genomic stability.
  • Nucleotide repeat instability, often linked to diseases, is associated with BER pathway activity.
  • Small molecules can modulate DNA repair pathways, offering therapeutic potential.

Purpose of the Study:

  • To investigate the in vitro effects of naphthyridine azaquinolone (NA) on the BER pathway.
  • To determine if NA interacts with deaminated CAG repeat sequences.
  • To explore the potential of NA in modulating nucleotide repeat instability.

Main Methods:

  • In vitro DNA binding assays using thermal melting analysis.
  • Assessing the impact of NA on UNG2- and APE1-catalyzed reactions within the BER pathway.
  • Utilizing deaminated 5'-CAG-3'/5'-CAG-3' DNA triads and hairpin structures.

Main Results:

  • Naphthyridine azaquinolone (NA) demonstrated binding to deaminated CAG repeat triads in DNA.
  • NA binding to a deaminated CAG repeat hairpin structure was observed.
  • NA partially inhibited the enzymatic activity of UNG2 and APE1 in the BER pathway.

Conclusions:

  • Naphthyridine azaquinolone (NA) interacts with damaged DNA repeat sequences.
  • NA's inhibition of key BER enzymes (UNG2, APE1) suggests a role in DNA repair modulation.
  • NA may offer a mechanism for inducing CAG repeat contraction via the BER pathway.
Keywords:
Base excision repairHuntington diseaseSmall moleculeTrinucleotide repeat

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