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

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.

HDACi mediate UNG2 depletion, dysregulated genomic uracil and altered expression of oncoproteins and tumor suppressors in B- and T-cell lines

“…Our findings establish UNG2 as a novel and ubiquitous target for HDACi-mediated degradation. This may expand indications for HDACi towards synthetic lethality in APOBEC3B expressing tumors [10] and to increase efficiency of deaminase-mediated CRISPR-Cas9 gene therapy [11]. Our results may also aid efforts to purge HIV viruses from latent reservoirs and treatment of autoimmune disease.…”

“…Finally, depletion of UNG was recently shown to induce synthetic lethality in APOBEC3B overexpressing cancers [10]. Many cancers overexpress APOBEC3B or harbor high kataegis mutational signatures conforming to deamination by the APOBEC/AID family of cytidine deaminases.…”

“…Lack of UNG mediates B-cell lymphoma in mice [33] and compromised immunoglobulin (Ig) CSR in humans due to impaired UNG2-mediated excision of uracils induced by activation induced deaminase (AID) at Ig switch regions [34]. UNG2 loss may also aggravate genomic instability in APOBEC3B expressing cancers [10]. Notably, three of the four proteins that helps activate the T-cell receptor (TCR) in the TCR complex CD3E (CD3ε), CD247 (CD3ζ) and CD3D (CD3δ) were among the ten most downregulated (1.9-fold) in Jurkat following SAHA treatment (Table 2), in agreement with earlier findings [35] and may explain the mono-therapy effects of HDACis in peripheral T-cell lymphomas such as CTCL, where T cell receptor activation can be a sustaining factor [36].…”

Base excision repair and its implications to cancer therapy

“…APOBEC3B is a cytosine deaminase that converts cytosine to uracil and causes an accumulation of C to T signature mutations in cancer genomes. A knockout of UNG has been demonstrated to kill APOBEC3B expressing cells due to an accumulation of uracil lesions in a mechanism dependent on non-canonical mismatch repair (MMR) [ 20 ]. Consequently, there is a need to develop specific small molecule inhibitors to UNG.…”

APOBEC3B and SPAG5, the Target Genes of miR-539, Involved into Imatinib-Resistant of Gastrointestinal Stromal Tumors

“…Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3B (APOBEC3B), an antiviral cytidine deaminase that induces DNA mutations, was considered as a medium for cancer development and therapeutic resistance [36]. Recent study have shown that the overexpression of APOBEC3B in tumor increased the resistance to chemotherapy and triggered anti-tumor T cells [37].…”