The deaminase APOBEC3B triggers the death of cells lacking uracil DNA glycosylase

Artur A. Serebrenik, Gabriel J. Starrett, Sterre Leenen, Matthew C. Jarvis, Nadine M. Shaban, Daniel J. Salamango, Hilde Nilsen, William L. Brown, Reuben S. Harris

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Human cells express up to 9 active DNA cytosine deaminases with functions in adaptive and innate immunity. Many cancers manifest an APOBEC mutation signature and APOBEC3B (A3B) is likely the main enzyme responsible. Although significant numbers of APOBEC signature mutations accumulate in tumor genomes, the majority of APOBEC-catalyzed uracil lesions are probably counteracted in an error-free manner by the uracil base excision repair pathway. Here, we show that A3B-expressing cells can be selectively killed by inhibiting uracil DNA glycosylase 2 (UNG) and that this synthetic lethal phenotype requires functional mismatch repair (MMR) proteins and p53. UNG knockout human 293 and MCF10A cells elicit an A3B-dependent death. This synthetic lethal phenotype is dependent on A3B catalytic activity and reversible by UNG complementation. A3B expression in UNG-null cells causes a buildup of genomic uracil, and the ensuing lethality requires processing of uracil lesions (likely U/G mispairs) by MSH2 and MLH1 (likely noncanonical MMR). Cancer cells expressing high levels of endogenous A3B and functional p53 can also be killed by expressing an UNG inhibitor. Taken together, UNG-initiated base excision repair is a major mechanism counteracting genomic mutagenesis by A3B, and blocking UNG is a potential strategy for inducing the selective death of tumors.

Original languageEnglish (US)
Pages (from-to)22158-22163
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number44
DOIs
StatePublished - Oct 29 2019

Keywords

  • APOBEC3B mutagenesis
  • DNA deamination
  • Mismatch repair
  • Synthetic lethality
  • Uracil base excision repair

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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