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Ongoing mutation drives cellular transformation. A cartoon depicting the transformation of a normal cell into a mass of tumor cells. Cellular changes are represented by altered morphologies and ever-increasing shades of red, due to ongoing mutational processes represented by the inset arrow.
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Cancer genomic DNA sequences enable identification of all mutations and suggest targets for precision medicine. The identities and patterns of the mutations themselves also provide critical information for deducing the originating DNA damaging agents, causal molecular mechanisms, and thus additional therapeutic targets. A classic example is ultravi...
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Context 1
... mutations, by and large, occur randomly across the genome over the course of an individual's lifetime. In some instances, however, the 'wrong combination' of som- atic mutations can transform a normal cell into a tumor cell ( Figure 1). The ongoing accumulation of additional mutations also contributes to the growth of local tumor cells, the development of metastatic outgrowths, and the emergence of therapy resistance. ...
Similar publications
APOBEC3B is a newly identified source of mutation in many cancers, including breast, head/neck, lung, bladder, cervical, and ovarian. APOBEC3B is a member of the APOBEC3 family of enzymes that deaminate DNA cytosine to produce the pro-mutagenic lesion, uracil. Several APOBEC3 family members function to restrict virus replication. For instance, APOB...
Although APOBEC3 cytidine deaminases A3G, A3F, A3D and A3H are packaged into virions and inhibit viral replication by inducing G-to-A hypermutation, it is not known whether they are copackaged and whether they can act additively or synergistically to inhibit HIV-1 replication. Here, we showed that APOBEC3 proteins can be copackaged by visualization...
Citations
... However, recent evidence shows that at least two A3 members (A and B) are capable of targeting cellular genomic DNA in human cancers to elicit C-to-T and C-to-G mutations in preferred trinucleotide contexts (TCA and TCT), resulting in "APOBEC signature" mutations prevalent in over half of tumor types. Over the past decade, the expression of A3A/B and/or the presence APOBEC signature mutations has been associated with tumor development, metastasis, drug resistance, and poor clinical outcomes (1)(2)(3)(4). These associative studies have been supported by work in mice where expression of catalytically active human A3A or A3B triggers APOBEC signature mutations and elevated tumor loads (5)(6)(7)(8). ...
Over the past decade, the connection between APOBEC3 cytosine deaminases and cancer mutagenesis has become increasingly apparent. This growing awareness has created a need for biochemical tools that can be used to identify and characterize potential inhibitors of this enzyme family. In response to this challenge, we have developed a Real-time APOBEC3-mediated DNA Deamination (RADD) assay. This assay offers a single-step set-up and real-time fluorescent read-out, and it is capable of providing insights into enzyme kinetics and also offering a high-sensitivity and easily scalable method for identifying APOBEC3 inhibitors. This assay serves as a crucial addition to the existing APOBEC3 biochemical and cellular toolkit and possesses the versatility to be readily adapted into a high-throughput format for inhibitor discovery.
... Kataegis hypermutation typically comprises C>N mutations in a TpC context 1 , although a T>N conversion in a TpT or CpT process attributed to error-prone polymerases has also been reported 7 as well as rare occurrences of an alternative kataegis form with a base substitution pattern most closely matching SBS signature 9 4 . Kataegis is proposed to be due to the dominant acting apolipoprotein B editing catalytic subunit 3b (APOBEC3B) enzyme that deaminates genomic DNA cytosines and promotes mutation rates higher than normal 8 . Kataegis is typically defined by an intermutation distance between adjacent SBSs, e.g., as six or more consecutive mutations with an average intermutation distance of ≤1000 bp 2 . ...
Kataegis is a hypermutation phenomenon characterized by localized clusters of single base pair substitution (SBS) reported in multiple cancer types. Despite a high frequency in breast cancer, large-scale analyses of kataegis patterns and associations with clinicopathological and molecular variables in established breast cancer subgroups are lacking. Therefore, WGS profiled primary breast cancers ( n = 791) with associated clinical and molecular data layers, like RNA-sequencing data, were analyzed for kataegis frequency, recurrence, and associations with genomic contexts and functional elements, transcriptional patterns, driver alterations, homologous recombination deficiency (HRD), and prognosis in tumor subgroups defined by ER, PR, and HER2 / ERBB2 status. Kataegis frequency was highest in the HER2-positive(p) subgroups, including both ER-negative(n)/positive(p) tumors (ERnHER2p/ERpHER2p). In TNBC, kataegis was neither associated with PAM50 nor TNBC mRNA subtypes nor with distant relapse in chemotherapy-treated patients. In ERpHER2n tumors, kataegis was associated with aggressive characteristics, including PR-negativity, molecular Luminal B subtype, higher mutational burden, higher grade, and expression of proliferation-associated genes. Recurrent kataegis loci frequently targeted regions commonly amplified in ER-positive tumors, while few recurrent loci were observed in TNBC. SBSs in kataegis loci appeared enriched in regions of open chromatin. Kataegis status was not associated with HRD in any subgroup or with distinct transcriptional patterns in unsupervised or supervised analysis. In summary, kataegis is a common hypermutation phenomenon in established breast cancer subgroups, particularly in HER2p subgroups, coinciding with an aggressive tumor phenotype in ERpHER2n disease. In TNBC, the molecular implications and associations of kataegis are less clear, including its prognostic value.
... This abasic site can be repaired with high or low fidelity, which may remove any effect of the uracil or cause the conversion of the C to A, G, or T (9). While the versatility of uracil in nucleating diverse downstream events is usually used as an advantage, some nuclear-localized APOBECs can aberrantly deaminate genomic DNA during replication or transcription and this has been linked to ongoing mutagenic processes in tumors and cancer evolution (12). Some A3 enzymes can also promote genomic instability in the absence of deamination, but the mechanism is not known (13). ...
Human APOBEC3 enzymes are a family of single-stranded (ss)DNA and RNA cytidine deaminases that act as part of the intrinsic immunity against viruses and retroelements. These enzymes deaminate cytosine to form uracil which can functionally inactivate or cause degradation of viral or retroelement genomes. In addition, APOBEC3s have deamination-independent antiviral activity through protein and nucleic acid interactions. If expression levels are misregulated, some APOBEC3 enzymes can access the human genome leading to deamination and mutagenesis, contributing to cancer initiation and evolution. While APOBEC3 enzymes are known to interact with large ribonucleoprotein complexes, the function and RNA dependence are not entirely understood. To further understand their cellular roles, we determined by affinity purification mass spectrometry (AP-MS) the protein interaction network for the human APOBEC3 enzymes and mapped a diverse set of protein–protein and protein–RNA mediated interactions. Our analysis identified novel RNA-mediated interactions between APOBEC3C, APOBEC3H Haplotype I and II, and APOBEC3G with spliceosome proteins, and APOBEC3G and APOBEC3H Haplotype I with proteins involved in tRNA methylation and ncRNA export from the nucleus. In addition, we identified RNA-independent protein-protein interactions with APOBEC3B, APOBEC3D, and APOBEC3F and the prefoldin family of protein-folding chaperones. Interaction between prefoldin 5 (PFD5) and APOBEC3B disrupted the ability of PFD5 to induce degradation of the oncogene cMyc, implicating the APOBEC3B protein interaction network in cancer. Altogether, the results uncover novel functions and interactions of the APOBEC3 family and suggest they may have fundamental roles in cellular RNA biology, their protein–protein interactions are not redundant, and there are protein-protein interactions with tumor suppressors, suggesting a role in cancer biology. Data are available via ProteomeXchange with the identifier PXD044275.
... This abasic site can be repaired with high or low fidelity, which may remove any effect of the uracil or cause the conversion of the C to A, G, or T (9). While the versatility of uracil in nucleating diverse downstream events is usually used as an advantage, some nuclear localized APOBECs can aberrantly deaminate genomic DNA during replication or transcription and this has been linked to ongoing mutagenic processes in tumors and cancer evolution (12). Some A3 enzymes can also promote genomic instability in the absence of deamination, but the mechanism is not known (13). ...
Human APOBEC3 enzymes are a family of single-stranded (ss)DNA and RNA cytidine deaminases that act as part of the intrinsic immunity against viruses and retroelements. These enzymes deaminate cytosine to form uracil which can functionally inactivate or cause degradation of viral or retroelement genomes. In addition, APOBEC3s have deamination independent antiviral activity through protein and nucleic acid interactions. If expression levels are misregulated, some APOBEC3 enzymes can access the human genome leading to deamination and mutagenesis, contributing to cancer initiation and evolution. While APOBEC3 enzymes are known to interact with large ribonucleoprotein complexes, the function and RNA dependence is not entirely understood. To further understand their cellular roles, we determined by affinity purification mass spectrometry (AP-MS) the protein interaction network for the human APOBEC3 enzymes and map a diverse set of protein-protein and protein-RNA mediated interactions. Our analysis identified novel RNA-mediated interactions between APOBEC3C, APOBEC3H Haplotype I and II, and APOBEC3G with spliceosome proteins, and APOBEC3G and APOBEC3H Haplotype I with proteins involved in tRNA methylation and ncRNA export from the nucleus. In addition, we identified RNA-independent protein-protein interactions with APOBEC3B, APOBEC3D, and APOBEC3F and the prefoldin family of protein folding chaperones. Interaction between prefoldin 5 (PFD5) and APOBEC3B disrupted the ability of PFD5 to induce degradation of the oncogene cMyc, implicating the APOBEC3B protein interaction network in cancer. Altogether, the results uncover novel functions and interactions of the APOBEC3 family and suggest they may have fundamental roles in cellular RNA biology, their protein-protein interactions are not redundant, and there are protein-protein interactions with tumor suppressors, suggesting a role in cancer biology.
... Kataegis hypermutation typically comprises C>N mutations in a TpC context [1], although a T>N conversion in a TpT or CpT process attributed to error-prone polymerases has also been reported [7]. Kataegis is proposed to be due to the dominant acting apolipoprotein B editing catalytic subunit 3b (APOBEC3B) enzyme that deaminates genomic DNA cytosines and promotes mutation rates higher than normal [8]. Kataegis is typically defined by an intermutation distance between adjacent SBSs, e.g., as six or more consecutive mutations with an average intermutation distance of less than or equal to 1,000 bp [2]. ...
Background Kataegis is a hypermutation phenomenon characterized by localized clusters of single base pair substitution (SBS) reported in multiple cancer types. Despite a high frequency in breast cancer, large scale analyses of kataegis patterns and associations with clinicopathological and molecular variables in established breast cancer subgroups are lacking. Methods WGS profiled primary breast cancers (n=791) with associated clinical and molecular data layers like RNA-sequencing data were analyzed. Kataegis frequency, recurrence, and associations with genomic contexts and functional elements, transcriptional patterns, driver alterations, homologous recombination deficiency (HRD), and prognosis were investigated in tumor subgroups defined by ER, PR, and HER2/ERBB2 status. Results Kataegis frequency was highest in the HER2-positive(p) subgroups, including both ER-negative(n)/positive(p) tumors (ERnHER2p/ERpHER2p). In TNBC, kataegis was neither associated with PAM50 nor TNBC mRNA subtypes, nor with distant relapse in chemotherapy treated patients. In ERpHER2n tumors, kataegis was associated with aggressive characteristics including PR-negativity, molecular Luminal B subtype, higher mutational burden, higher grade, and expression of proliferation-associated genes. Recurrent kataegis loci frequently targeted regions commonly amplified in ER-positive tumors, while few recurrent loci were observed in TNBC. SBSs in kataegis loci appeared enriched in regions of open chromatin. Kataegis status was not associated with HRD in any subgroup, or with distinct transcriptional patterns in unsupervised or supervised analysis. Conclusions Kataegis is a common hypermutation phenomenon in established breast cancer subgroups, particularly in HER2p subgroups, coinciding with an aggressive tumor phenotype in ERpHER2n disease. In TNBC, the molecular implications and associations of kataegis are less clear, including its prognostic value.
... Apolipoprotein B mRNA editing enzyme (abbreviated as APOBEC3B) is a human cytidine deaminase that has a role in innate immunity and has been linked to the mutagenesis of cancers (Hou et al., 2021). APOBEC3B is a nonessential human globular protein that is part of the larger APOBEC3 family and is responsible for the deamination of cytosine to uracil in single-stranded DNA (Harris, 2015). The catalytic site on APOBEC3B, characterized primarily by the presence of a zinc ion, binds cytosine noncovalently, catalyzes its conversion to uracil, and then releases the product. ...
... Human APOBEC3B natively mutates single stranded DNA (ssDNA), which prevents viral DNA from being used for viral replication and infecting the host (Kouno et al., 2017). Overexpression of APOBEC3B in humans causes damage to host DNA, leading to a variety of random mutations (Harris, 2015). Cancer can result from the accumulation of mutations caused by overexpression of APOBEC3B (NCI, 2023). ...
... Overactivation of APOBEC enzymes (usually APO-BEC3A and APOBEC3B) causes deamination of cytosine residues to uracil, which will be incorporated as a thymine as the cell divides, ultimately resulting in a C > T transversion (COSMIC signature 2) and hypermutation [59,60]. Generally, the C > T transversions occur at TCA or TCG regions [61]. The other APOBEC-related mutational signature, signature 13, is characterized by C > G mutations in the same TCA or TCG regions and is frequently found along with signature 2 [62]. ...
... Additionally, the presence of signature 2 mutations has been associated with previous tamoxifen exposure in breast cancer [41]. APO-BEC3B upregulation in estrogen-positive breast cancer predicts poorer outcomes after surgery and an overall lower response to therapy [61,69]. In contrast, signature 13 mutations, also associated with APOBEC activation, predict pathologic complete response in HR-positive breast cancer [70]. ...
... APOBEC3B is a DNA cytosine deaminase that contributes to gene mutations by converting cytosine to uracil [8]. In particular, overexpression and abnormal activation of APOBEC3B contribute to the progression of various cancers, including drug resistance [9][10][11]. In cervical cancer, high expression of APOBEC3B is associated with infection of HPV-18 and proliferation and hypomethylation of cyclin D1 in cervical cancer cells [12,13]. ...
... In PCa, deletion of the APOBEC3A/B allele has been shown to be associated with increased risk for PCa amongst individuals aged <50 years old, and this association was gradually reduced with increasing age [15]. Moreover, the upregulation of APO-BEC3B is associated with poor prognosis in human glioma and patients with oestrogen receptor-positive (ER+) breast cancer [9,16]. Also, overexpression of APOBEC3B promotes the development of temozolomide resistance in human glioma and tamoxifen resistance in patients with ER+ breast cancer [10,16]. ...
Docetaxel is one of the most commonly used drugs in prostate cancer (PCa) chemotherapy, but its therapeutic effect in PCa is usually limited due to its drug resistance. APOBEC3B is a DNA cytosine deaminase that can alter biological processes, including chemoresistance. APOBEC3B is upregulated in various cancers. However, the biological function and underlying regulation of APOBEC3B in PCa remain unclear. In this study, we explored the role of APOBEC3B in PCa chemoresistance and the molecular mechanism of its dysregulated expression. Our results revealed that APOBEC3B was upregulated in PCa docetaxel-resistant cells, while its knockdown significantly repressed cell proliferation and docetaxel resistance of PCa cells. Bioinformatics and luciferase report analysis showed that miR-138-5p targeted APOBEC3B. In addition, miR-138-5p overexpression impeded cell proliferation and docetaxel resistance in PCa, while miR-138-5p inhibitors reversed this process. Further studies showed that upregulation of APOBEC3B expression in docetaxel-resistant cells overexpressing miR-138-5p could desensitize PCa cells to docetaxel treatment. Taken together, miR-138-5p regulates PCa cell proliferation and chemoresistance by targeting the 3'-UTR of APOBEC3B, which may provide novel insights and therapeutic targets for the treatment of PCa.
... Within ssDNA, the various APOEBC3s deaminate cytosines in distinct trinucleotide contexts. For example, APOBEC3A and APOBEC3B-which are the major mutators-deaminate thiamine preceding cytosine (TpC) motifs; APOBEC3A preferentially acts on TpC motifs following pyrimidines, while APOBEC3B tends to deaminate TpC motifs after purines [20][21][22][23]. Following deamination, different cellular processes can create C-to-T and C-to-G mutations, which are defined as signatures 2 and 13 in COSMIC, respectively [24][25][26]. ...
... Following deamination, different cellular processes can create C-to-T and C-to-G mutations, which are defined as signatures 2 and 13 in COSMIC, respectively [24][25][26]. The former C-to-T transition is more common and arises from aberrant replication of uracil-containing DNA templates, while both substitutions can occur through erroneous repair of abasic sites generated by uracil glycosylase activity ( Fig. 1) [20,[27][28][29]. In addition to these conventionally defined APOBEC3-induced mutational signatures, APOBEC3G can cause C-to-T transitions at TCC, GCC, CCC, CCT, and GCG motifs ( Fig. 1) [30]. ...
... Erroneous replication and repair pathways can then generate mutational signatures 2 and 13. Repair by the translesion synthesis (TLS) polymerase REVI generates a C-to-G mutation (signature 13), while repair by other enzymes such as DNA polymerase δ, DNA polymerase ε, and TLS polymerase κ generates a C-to-T mutation (signature 2) [20]. Lower panel: The major mutators among the APOBEC3 superfamily have distinct substrate preferences defined mainly by trinucleotide context and ssDNA secondary structure Page 3 of 25 Butler and Banday Journal of Hematology & Oncology (2023) 16:31 APOBEC3s can promote immune-activated or immunosuppressed phenotypes, which may partially explain their varying prognostic significance across cancer types. ...
Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs) are cytosine deaminases involved in innate and adaptive immunity. However, some APOBEC family members can also deaminate host genomes to generate oncogenic mutations. The resulting mutations, primarily signatures 2 and 13, occur in many tumor types and are among the most common mutational signatures in cancer. This review summarizes the current evidence implicating APOBEC3s as major mutators and outlines the exogenous and endogenous triggers of APOBEC3 expression and mutational activity. The review also discusses how APOBEC3-mediated mutagenesis impacts tumor evolution through both mutagenic and non-mutagenic pathways, including by inducing driver mutations and modulating the tumor immune microenvironment. Moving from molecular biology to clinical outcomes, the review concludes by summarizing the divergent prognostic significance of APOBEC3s across cancer types and their therapeutic potential in the current and future clinical landscapes.
... Results revealed that DEGs were mainly enriched in the cell cycle, DNA replication, and chromosomal region, suggesting that APOBEC3B plays a role in cell proliferation. Previous studies have indicated that APOBEC3B can induce somatic mutations, which contribute to cancer pathogenesis [20][21][22][23][24]. A recent study revealed that APOBEC3B was predominantly expressed at the G2/M phase in myeloma and normal blood cells [25]. ...
Objective:
Cervical cancer is one of the leading fatal diseases in women, and the role of Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) in cervical cancer is uncertain.
Methods:
Four Gene Expression Omnibus (GEO) mRNA microarray datasets were analyzed to identify differentially expressed genes (DEGs) between cervical cancer and normal cervical tissues. The results were validated using a The Cancer Genome Atlas (TCGA)-cervical cancer (CESC) dataset. Expression profiles and patients' clinical data were used to investigate the relationship between APOBEC3B expression and cervical cancer survival. APOBEC3B co-expressed genes were subjected to enrichment analyses, and correlations between APOBEC3B expression and immunologic infiltrates were investigated using Tumor Immune Estimation Resource (TIMER). We generated receiver operating characteristic curve (ROC) curves to evaluate the performance of APOBEC3B expression in predicting cervical cancer prognosis.
Results:
Fourteen overlapping DEGs were obtained, and APOBEC3B was chosen as a candidate gene. TCGA data further confirmed that APOBEC3B was significantly increased in cervical cancer, relative to normal adjacent tissues, and this expression was associated with poor clinical outcome. Results from quantitative real time polymerase chain reaction (RT-qPCR) and immunohistochemical staining of cervical carcinoma tissues supported these findings. Enrichment analysis showed that APOBEC3B co-expressed genes were mainly enriched in cell cycle, DNA replication and chromosomal region. Moreover, APOBEC3B expression was significantly associated with T stage, M stage, primary therapy outcome and poor clinical prognosis in cervical cancer. Similarly, APOBEC3B was closely correlated with gene markers of diverse immune cells. APOBEC3B expression was an independent indicator of cervical cancer prognosis, according to univariate Cox and ROC analyses.
Conclusion:
High APOBEC3B expression is strongly related to a poor prognosis in cervical cancer patients.
