Evaluation of APOBEC3B Recognition Motifs by NMR Reveals Preferred Substrates

ACS Chem Biol. 2018 Sep 21;13(9):2427-2432. doi: 10.1021/acschembio.8b00639. Epub 2018 Aug 27.

Abstract

APOBEC3B (A3B) deamination activity on ssDNA is considered a contributing factor to tumor heterogeneity and drug resistance in a number of human cancers. Despite its clinical impact, little is known about A3B ssDNA substrate preference. We have used nuclear magnetic resonance to monitor the catalytic turnover of A3B substrates in real-time. This study reports preferred nucleotide sequences for A3B substrates, including optimized 4-mer oligonucleotides, and reveals a breadth of substrate recognition that includes DNA sequences known to be mutated in drug-resistant cancer clones. Our results are consistent with available clinical and structural data and may inform the design of substrate-based A3B inhibitors.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytidine Deaminase / chemistry
  • Cytidine Deaminase / metabolism*
  • DNA, Single-Stranded / chemistry
  • DNA, Single-Stranded / metabolism*
  • Humans
  • Minor Histocompatibility Antigens / chemistry
  • Minor Histocompatibility Antigens / metabolism*
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Nucleotides / chemistry
  • Nucleotides / metabolism*
  • Substrate Specificity

Substances

  • DNA, Single-Stranded
  • Minor Histocompatibility Antigens
  • Nucleotides
  • APOBEC3B protein, human
  • Cytidine Deaminase