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 language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Oct 29 2019|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank Salvatore Caradonna for providing rabbit anti-UNG polyclonal sera, Rick Fishel and Alan Ashworth for thoughtful comments, and James Stivers for providing a human UNG cDNA. These studies were supported by National Cancer Institute Grant P01-CA234228 (to R.S.H.), Norwegian Cancer Society Grant 182793 (to H.N.), and a Norwegian Centennial Chair Program grant (to R.S.H. and H.N.). R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor, and an Investigator of Howard Hughes Medical Institute.
© 2019 National Academy of Sciences. All rights reserved.
- APOBEC3B mutagenesis
- DNA deamination
- Mismatch repair
- Synthetic lethality
- Uracil base excision repair