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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 44; pp. 22158 - 22163
• Main Authors: Serebrenik, Artur A., Starrett, Gabriel J., Leenen, Sterre, Jarvis, Matthew C., Shaban, Nadine M., Salamango, Daniel J., Nilsen, Hilde, Brown, William L., Harris, Reuben S.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.10.2019
• Subjects: APOBEC Deaminases; Base excision repair; Biological Sciences; Catalytic activity; Cell Death; Cell Line, Tumor; Complementation; Cytidine Deaminase - genetics; Cytosine; Death; Deoxyribonucleic acid; DNA; DNA glycosylase; DNA Glycosylases - antagonists & inhibitors; DNA Glycosylases - genetics; DNA Mismatch Repair; DNA Repair; Gene expression; Gene Knockout Techniques; Genomes; Humans; Innate immunity; Lesions; Lethality; Mismatch repair; MLH1 protein; Models, Molecular; Mortality; MSH2 protein; Mutagenesis; Mutation; Null cells; p53 Protein; Phenotypes; Repair; Tumors; Ubiquitination; Uracil; Uracil-DNA glycosidase; DNA deamination; mismatch repair; uracil base excision repair; synthetic lethality; APOBEC3B mutagenesis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1904024116

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.