Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A

Stefan Harjes, Harikrishnan M. Kurup, Amanda E. Rieffer, Maitsetseg Bayarjargal, Jana Filitcheva, Yongdong Su, Tracy K. Hale, Vyacheslav V. Filichev (), Elena Harjes (), Reuben S. Harris () and Geoffrey B. Jameson ()
Additional contact information
Stefan Harjes: Massey University
Harikrishnan M. Kurup: Massey University
Amanda E. Rieffer: University of Minnesota–Twin Cities
Maitsetseg Bayarjargal: Massey University
Jana Filitcheva: Massey University
Yongdong Su: Massey University
Tracy K. Hale: Massey University
Vyacheslav V. Filichev: Massey University
Elena Harjes: Massey University
Reuben S. Harris: University of Texas Health San Antonio
Geoffrey B. Jameson: Massey University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The normally antiviral enzyme APOBEC3A is an endogenous mutagen in human cancer. Its single-stranded DNA C-to-U editing activity results in multiple mutagenic outcomes including signature single-base substitution mutations (isolated and clustered), DNA breakage, and larger-scale chromosomal aberrations. APOBEC3A inhibitors may therefore comprise a unique class of anti-cancer agents that work by blocking mutagenesis, slowing tumor evolvability, and preventing detrimental outcomes such as drug resistance and metastasis. Here we reveal the structural basis of competitive inhibition of wildtype APOBEC3A by hairpin DNA bearing 2′-deoxy-5-fluorozebularine in place of the cytidine in the TC substrate motif that is part of a 3-nucleotide loop. In addition, the structural basis of APOBEC3A’s preference for YTCD motifs (Y = T, C; D = A, G, T) is explained. The nuclease-resistant phosphorothioated derivatives of these inhibitors have nanomolar potency in vitro and block APOBEC3A activity in human cells. These inhibitors may be useful probes for studying APOBEC3A activity in cellular systems and leading toward, potentially as conjuvants, next-generation, combinatorial anti-mutator and anti-cancer therapies.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-42174-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42174-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-42174-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().