Abstract
BackgroundThe APOBEC gene family of cytidine deaminases plays important roles in DNA repair and mRNA editing. In many cancers, APOBEC3B increases the mutation load, generating clusters of closely spaced, single-strand-specific DNA substitutions with a characteristic hypermutation signature. Some studies also suggested a possible involvement of APOBEC3A, REV1, UNG, and FHIT in molecular processes affecting APOBEC mutagenesis. It is important to understand how mutagenic processes linked to the activity of these genes may affect sensitivity of cancer cells to treatment.ResultsWe used information from the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer resources to examine associations of the prevalence of APOBEC-like motifs and mutational loads with expression of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT and with cell line chemosensitivity to 255 antitumor drugs. Among the five genes, APOBEC3B expression levels were bimodally distributed, whereas expression of APOBEC3A, REV1, UNG, and FHIT was unimodally distributed. The majority of the cell lines had low levels of APOBEC3A expression. The strongest correlations of gene expression levels with mutational loads or with measures of prevalence of APOBEC-like motif counts and kataegis clusters were observed for REV1, UNG, and APOBEC3A. Sensitivity or resistance of cell lines to JQ1, palbociclib, bicalutamide, 17-AAG, TAE684, MEK inhibitors refametinib, PD-0325901, and trametinib and a number of other agents was correlated with candidate gene expression levels or with abundance of APOBEC-like motif clusters in specific cancers or across cancer types.ConclusionsWe observed correlations of expression levels of the five candidate genes in cell line models with sensitivity to cancer drug treatment. We also noted suggestive correlations between measures of abundance of APOBEC-like sequence motifs with drug sensitivity in small samples of cell lines from individual cancer categories, which require further validation in larger datasets. Molecular mechanisms underlying the links between the activities of the products of each of the five genes, the resulting mutagenic processes, and sensitivity to each category of antitumor agents require further investigation.
Highlights
The Apolipoprotein B mRNA-editing enzyme (APOBEC) gene family of cytidine deaminases plays important roles in DNA repair and mRNA editing
We refer to the three sequence motifs, T(C>K)W, T(C>D)R, and T(C>D)D which were analyzed in this study, as APOBEC-like motifs, in order to distinguish them from the APOBEC mutational signature term, which commonly refers to a matrix of mutational changes that are characteristic of APOBEC activity in the 96-trinucletide format [14, 44]
Examination of gene expression measures in the pan-cancer dataset showed a bimodal distribution of APOBEC3B expression (Fig. 2b), whereas APOBEC3A, REV1, uracil DNA glycosylase (UNG), and fragile histidine triad protein (FHIT) had unimodal distributions of their expression measures (Fig. 2a, c–e)
Summary
The APOBEC gene family of cytidine deaminases plays important roles in DNA repair and mRNA editing. APOBEC3B increases the mutation load, generating clusters of closely spaced, singlestrand-specific DNA substitutions with a characteristic hypermutation signature. APOBEC3A and APOBEC3B (apolipoprotein B mRNAediting enzymes 3A and 3B, catalytic polypeptide-like) are cytosine deaminases from the AID/APOBEC family, members of which play important roles in host immunity against pathogens [1, 2]. The activity of multiple members of the AID/APOBEC family including APOBEC3A but not APOBEC3B has been linked to epigenetic processes involving DNA demethylation via deamination of 5-hydroxymethyl-cytozine (5-hmC) to 5-hydroxymethyluracil (5-hmU) [1, 3, 4]. In multiple human cancer categories, increased APOBEC3B gene expression has been associated with genome-wide hypermutation and with kataegis, a mutagenic process that generates clusters of closely spaced, single-strand-specific DNA substitutions, which are predominantly C to T [5, 6]. Increased APOBEC3B gene expression, germline polymorphisms in the APOBEC3 genome region, and higher degree of abundance of APOBEC3B mutational signatures have been associated with increased cancer risk and patient survival [5, 7]
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