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Evaluation of APOBEC3B Recognition Motifs by NMR Reveals Preferred Substrates

Manjuan Liu1, Aurélie Mallinger1, Marcello Tortorici1

  • 1Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SM2 5NG , U.K.

ACS Chemical Biology
|August 22, 2018
PubMed

Insights

The study identified preferred DNA sequences for APOBEC3B (A3B) enzyme activity, which drives tumor heterogeneity and drug resistance. Understanding these A3B substrate preferences can help develop new cancer therapies.

Area of Science:

  • Biochemistry
  • Genetics
  • Molecular Biology

Background:

  • APOBEC3B (A3B) deamination activity on single-stranded DNA (ssDNA) contributes to tumor heterogeneity and drug resistance in various cancers.
  • The specific substrate preferences of A3B remain largely uncharacterized, hindering therapeutic development.

Discussion:

  • This study utilized nuclear magnetic resonance (NMR) to observe A3B's real-time catalytic turnover on ssDNA substrates.
  • The research identified preferred nucleotide sequences for A3B, including optimized 4-mer oligonucleotides.
  • A3B demonstrates broad substrate recognition, encompassing DNA sequences previously found mutated in drug-resistant cancer clones.

Key Insights:

  • NMR-based real-time monitoring reveals A3B's ssDNA substrate sequence preferences.
  • Identified preferred 4-mer oligonucleotide sequences for A3B activity.
  • A3B recognizes DNA sequences associated with cancer drug resistance.

Outlook:

  • Findings align with existing clinical and structural data on A3B.
  • Results may guide the design of novel substrate-based A3B inhibitors for cancer treatment.

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