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. 2020 Aug 9;146(11):2721–2730. doi: 10.1007/s00432-020-03348-x

Activation-induced cytidine deaminase: in sickness and in health

Leonardo Alves de Souza Rios 1, Benjamin Cloete 1, Shaheen Mowla 1,✉
PMCID: PMC11804718  PMID: 32772231

Abstract

Activation Induced cytidine Deaminase (AID) is an essential enzyme of the adaptive immune system. Its canonical activity is restricted to B lymphocytes, playing an essential role in the diversification of antibodies by enhancing specificity and changing affinity. This is possible through its DNA deaminase function, leading to mutations in DNA. In the last decade, AID has been assigned an additional function: that of a powerful DNA demethylator. Adverse cellular conditions such as chronic inflammation can lead to its deregulation and overexpression. It is an important driver of B-cell lymphoma due to its natural ability to modify DNA through deamination, leading to mutations and epigenetic changes. However, the deregulation of AID is not restricted to lymphoid cells. Recent findings have provided new insights into the role that this protein plays in the development of non-lymphoid cancers, with some research shedding light on novel AID-driven mechanisms of cellular transformation. In this review, we provide an updated narrative of the normal physiological functions of AID. Additionally, we review and discuss the recent research studies that have implicated AID in carcinogenesis in varying tissue types including lymphoid and non-lymphoid cancers. We review the mechanisms, whereby AID promotes carcinogenesis and highlight important areas of future research.

Keywords: Activation induced cytidine deaminase, Deaminase, Demethylator, Lymphomagenesis, Cancer

Background

The human body is constantly challenged by millions of antigens and requires an efficient way of protecting itself from potential infection. This is achieved by the adaptive immune system, that can be rapidly modified to prevent and combat infections. Adaptive immunity is mediated through the B and T lymphocytes which collaborate to generate a large repertoire of specific antibodies able to recognise foreign antigens (Chandra et al. 2015). After naïve B cells encounter antigens in secondary lymphoid tissues, two processes occur, somatic hypermutation (SHM) and class switch recombination (CSR). The Activation Induced cytidine Deaminase (AID) enzyme, a member of the Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) family of RNA/DNA editing enzymes, plays a central role in these diversification mechanisms (Muramatsu et al. 2000). Tight regulation of AID expression and enzymatic activity is imperative due to its intrinsic DNA modifying ability. However, a plethora of reports describing AID deregulation in varying tissue types have been published, with its deregulation being highly associated with malignant transformation. This review will focus on recent findings related to AID deregulation in different cancer types and the functional effects on cellular activity thereof.

The physiological function of AID

During SHM point mutations are introduced into the variable region of the Immunoglobulin IgH and IgL genes at “hot spot motifs” RGYW/WRCY with R = A/G, Y = C/T and W = A/T by a rate of up to 10−3–10−4 mutations per base/division, greater than the background 10−9 rate of mutation within the rest of the genome (Sablitzky et al. 1985; Chaudhuri et al. 2014). When AID reaches its target ssDNA substrate it converts deoxycytidine (dC) in the variable region to deoxyuridine (dU), creating a base mismatch that elicits error-prone repair through the Base Excision Repair (BER) and Mismatch Repair (MMR) pathways. Mutations also occur when replication proceeds before the correction of mismatches resulting in a C:G–T:A transition (Petersen-Mahrt et al. 2002; Neuberger et al. 2003; Yu et al. 2004). Effector function of antibodies is changed through CSR, a process that occurs between two switch regions (S) found upstream of each constant heavy chain (CH) gene. The intervening DNA is excised as a switch circle, resulting in the variable region being juxtaposed to the downstream CH gene. AID converts dC–dU and these are removed by the actions of Uracil-DNA Glycosylase (UNG) and apyrimidinic endonuclease (APE1) leaving ssDNA breaks, dsDNA breaks are formed when ssDNA breaks are close to each other on opposite DNA strands or by MMR repair pathway, these are then joined by either non-homologous end-joining (NHEJ) or alternative end-joining (A-EJ) processes (Fear 2013). Together, SHM and CSR produce highly specific antibodies with different effector functions and is, therefore, essential for humoral immunity. More recently, AID has become recognised as a DNA demethylator, linked to its ability to deaminate cytidine (Rai et al. 2008; Ramiro and Barreto 2015). During B cell passage through the Germinal Centre (GC) changes in methylation occur at B cell-specific loci, potentially in an AID dependant manner (Dominguez et al. 2015). Owing to its mutative capacity, at both genetic and epigenetic levels, AID is a clear threat to genomic stability, requiring strict regulation to prevent “off-target” modifications, predisposing cells to malignant transformation (Nagaoka et al. 2010).

Physiological regulation of AID expression

The regulation of AID expression occurs at multiple levels. Four conserved regions in the AICDA gene locus have been described, containing a variety of transcription factor binding sites. Region one, located directly upstream of the transcription start site (TSS), contains binding sites for transcription factors such as Sp1, Sp3 and HoxC4-OCT, and is believed to mediate basal AID expression along with Region three located 25-kb downstream of exon 5. Region two carries strong repressive elements in the first intron and recruits repressive factors such as E2F and c-MYB (Tran et al. 2010). Region four is located 8-kb upstream of the TSS and has been described to mediate AID expression following B cell activation via CD40L and IL-4 signalling, through binding of transcription factors such as NFκB and STAT6, respectively (Lee-Theilen and Chaudhuri 2010; Nagaoka et al. 2010). Regulation of AID also occurs post-transcriptionally by the repressive action of miRNAs. To date, five miRNAs have been implicated in the repression of AID namely: miR-155, miR-361, miR-93, miR-29b and miR-181b (de Yébenes et al. 2008; Dorsett et al. 2008; Teng et al. 2008; Borchert et al. 2011; Basso et al. 2012; Recaldin et al. 2018). Post-translational regulation of AID is mediated by proteins like the Protein Kinase A (PKA) (Pasqualucci et al. 2006), with phosphorylation of S38, T140, T27 and S3 being important for AID function during SHM and CSR (McBride et al. 2006; Demorest et al. 2011; Gazumyan et al. 2011; Mu et al. 2017). AID is predominantly localised to the cytoplasm of B cells, where its stabilization is dependent on Heat shock protein 90 (Hsp90) coupling (Orthwein et al. 2010). However, AID acts on ssDNA and is, therefore, shuttled into and out of the nucleus through its nuclear localization signal (NLS) and nuclear export signal (NES) located in the N and C termini, respectively (Ito et al. 2003). Furthermore, AID activity is limited by the cell cycle, in early G1 phase when chromatin de-condense and transcription reinitiates, ssDNA is exposed allowing AID access to its preferred substrate (Wang et al. 2017). Off-target AID activity is then limited when the nuclear envelope reforms and AID molecules are shuttled out of the nucleus by a Chromosome Maintenance 1 (CRM-1) dependant mechanism or rapidly degraded in the nucleus via a ubiquitin- and ATP- independent proteasomal degradation pathway mediated by REGgamma (REG-γ) or through ubiquitination by Cullin seven E3 ubiquitin ligase (McBride et al. 2004; Uchimura et al. 2011; Wang et al. 2017; Luo et al. 2019) Together, these levels of regulation ensure that AID expression remains in check.

AID in epigenetics

Within its repertoire of capabilities, AID can bring about epigenetic alterations and much evidence supports its role in DNA demethylation. This has been an exciting recent topic in the field, and notably, the role of AID in cancer, particularly in lymphomagenesis, has been linked to its demethylating function, which will be discussed in more detail in following sections (Dominguez and Shaknovich 2014). In systems that are subject to epigenetic reprogramming, such as oocytes and pluripotent stem cells, AID mRNA has been measured at relatively high levels, with AID’s ability to deaminate 5-methylcytosine (5mC)d confirmed using in vitro assays (Morgan et al. 2004). Other studies have found the enzyme to be implicated in the epigenetic reprogramming of mouse embryonic stem cells, zebrafish DNA demethylation as well as DNA demethylation in mouse primordial germ cells (Rai et al. 2008; Bhutani et al. 2010; Popp et al. 2010).

AID is a key driver of lymphoid cancers

The involvement of AID in lymphoid malignancies has been well described, with aberrant expression described in both B and T cell-derived lymphomas (Bödör et al. 2005; Nakamura et al. 2011). However, two Non-Hodgkin Lymphomas (NHL) of mature B cell origin, namely Burkitt Lymphoma (BL) and Diffuse Large B Cell Lymphoma (DLBCL) are mostly implicated (Takizawa et al. 2008; Nagaoka et al. 2010).

AID and Burkitt Lymphoma

A clear link exists between AID and the characteristic translocation of c-MYC in BL. This highly aggressive B cell lymphoma occurs in three main forms: endemic type (eBL), sporadic type (sBL) and immunodeficiency related such as HIV-associated BL (HIV-BL). The main translocation event, t(8;14) in human BL and t(12;15) in murine plasmacytomas involving the c-MYC and IgH loci and common to all three variants is driven by AID (Ramiro et al. 2004; Robbiani et al. 2008; Takizawa et al. 2008; Greisman et al. 2012). The mechanistic evidence for the role of AID in c-MYC translocations has been demonstrated in vitro. Duquette et al. (2005) showed, using electron microscopy, that AID binds G-loops that form during transcription of the c-MYC gene as well as the immunoglobulin S region. These G-loop regions were mapped to the breakpoints related to c-MYC translocation. Furthermore, AID mutational activity has also been reported in the ID3 gene resulting in the inactivation of this important B cell regulator (Richter et al. 2012).

Infection with the human gammaherpesvirus Epstein-Barr virus (EBV) is closely associated with eBL, where it has been shown to provide a growth advantage to cells following the c-MYC-IGH translocation event by blocking apoptosis (Epstein et al. 1965). Subsequently, further studies suggested that EBV directly targets AID (Epeldegui et al. 2007b; Heath et al. 2012). This relationship is reliant on the latency program of EBV infection that differs according to the lymphoproliferative malignancy (Hui et al. 2019). For instance, the EBV protein Latent Membrane Protein 1 (LMP1) that is constitutively expressed during the latency II and III programs, promotes AID activity by mimicking CD40 signalling (He et al. 2003; Rastelli et al. 2008). LMP1 was also shown to enhance AID transcription via increased binding of the EGR-1 transcription factor to the AICDA promoter (Kim et al. 2013). Contrarily, the latency III specific Epstein-Bar nuclear antigen A2 (EBNA2) protein inhibits AID expression during EBV driven B cell expansion (Tobollik et al. 2006). More recently, another latency III specific factor, the Epstein-Barr virus nuclear antigen 3C (EBNA3C), was shown to interact with recombination binding protein (RBPJ), a transcription factor of the Notch pathway, and bind to conserved regulatory regions within the AICDA locus, eliciting epigenetic modifications and culminating in increased SHM activity (Kalchschmidt et al. 2016). A genome-wide sequencing study recently revealed that EBV status has a significant impact on the genetic landscape of paediatric BL, potentially superseding clinical variant status. Here it was shown that both EBV positive eBL and sBL had higher levels of AICDA expression, correlated with increased aberrant SHM activity (Grande et al. 2019). These studies highlight the complex relationship between EBV factors and AID expression and support a collaborative role between EBV and AID in lymphomagenesis.

The majority of eBL cases occurs in regions heavily burdened by malaria, including equatorial Africa, Papua New Guinea and Northern Brazil, where it is the most prevalent cancer among children in these regions (Orem et al. 2007; Molyneux et al. 2012). Therefore, concomitant infection with P.falciparum, the causative agent for malaria, and EBV is a common feature of eBL (Chêne et al. 2007; Aguilar et al. 2017). Interestingly, the sickle cell trait that confers protection against malaria has also been shown to correlate with decreased eBL risk (Legason et al. 2017). The mechanism behind this phenomenon is not well understood, but recent studies point to deregulation of AID by P. falciparum as a potential contributor to disease. Torgbor et al. (2014) showed that Tonsil B cells incubated with combined P. falciparum extract, CD40 and IL-4 expressed high levels of AID mRNA compared to cells incubated with only CD40 and IL-4 or with the toll-like receptor 9 (TLR9) CpG control which is known to activate AID. The authors suggested that induction of AID expression by P. falciparum is dependent on T cell help and occurs in the GC, where eBL originates. Furthermore, they identified Haemozoin, a component of the P. falciparum extract, as a potential AID agonist. Another study using mutant mice carrying B cell-specific deficiencies (CD19Cre/+ and p53lox/lox), with either AID deficiency (AID−/−) or proficiency (AID+/+), showed that infection by P. chabaudi, the murine malaria parasite, leads to extended expansion of GCs, resulting in accumulation of DNA damage and translocations. Although AID-deficient mice developed lymphomas at the same rate as AID proficient mice, the presence of AID favoured the development of mature B cell malignancies in persistently infected mice (Robbiani et al. 2015). These studies, therefore, suggest that infection by malaria parasites promotes a microenvironment for mature B cell transformation via a mechanism that involves AID.

The risk of developing BL is significantly increased with HIV infection and while the mechanism, whereby immunodeficiency increases the risk for BL is not entirely clear, it is likely linked to EBV infection. However, a substantial proportion of HIV-BL cases are not EBV positive, with only a reported 40–60% of HIV-associated BL from the USA and Western Europe being EBV positive (Bornkamm 2009). With the introduction and global expansion of Highly Active Antiretroviral Therapy (HAART), there has been a generalised decrease in AIDS-defining cancers due to reconstitution of the immune system. Notably, a similar decline in BL incidence has not been observed and still accounts for a substantial proportion of HIV-associated NHL in the HAART era (Petrich et al. 2012; Rodrigo et al. 2012; Dhokotera et al. 2019). Interestingly, AID expression was shown to be elevated in the peripheral blood mononuclear cells of HIV positive patients even before the development of lymphoma, with the expression of AID being highest in those who developed Burkitt lymphoma (Epeldegui et al. 2007a). Although HIV has been shown to induce AID via the binding of human CD40L which becomes incorporated onto virions (Epeldegui et al. 2010), recent studies suggest a more direct role. There is mounting evidence supporting an oncogenic role for HIV, largely attributed to the activity of its viral proteins (Germini et al. 2017; El-Amine et al. 2018). For instance, Sall et al. (2019) showed an increase in AICDA expression in B lymphocytes exposed extracellularly to the HIV-1 Transactivator of transcription (Tat) protein. Importantly, the increase in AICDA expression by Tat correlated with increased lesions at the c-MYC and IgH loci, followed by induction of NHEJ, indicative of DNA repair consequent to AID CSR activity. In a recent study by Epeldegui et al. (2019), a subset of B cells characterised by IL10 secretion, and expression of the programmed cell death ligand-1 (PD-L1) were found to be elevated in the PBMC of HIV positive patients who went on to develop NHL, compared to controls (Epeldegui et al. 2019). Furthermore, the group also showed that HIV could directly induce PD-L1 on B cells through CD40L interaction. Interestingly, an earlier study by Bi et al. (2016) showed that PD-L1 is upregulated by LMP1, albeit in the context of T-Cell lymphoma. In another recent study, EBNA2, but not LMP1, was shown to enhance the expression of PD-L1 in a DLBCL model. It would, therefore, be interesting to investigate the involvement of AID within these axes (Anastasiadou et al. 2019).

AID in DLBCL

Like BL, DLBCL is a GC derived lymphoma with a very high degree of molecular heterogeneity. The disease is categorised into two broad types, namely Activated B Cell Like (ABC)-DLBCL and Germinal Centre B Cell-Like (GCB)- DLBCL, with ABC-DLBCL being the more aggressive type. AID’s involvement in the development of DLBCL has been studied, with signatures of AID mutational activity being found in many genes including BCL6, PIM1, cMYC, RHOH and PAX5 (Pasqualucci et al. 2001; Liu et al. 2008). Furthermore, whole-exome sequencing has implicated AID in the mutation of genes involved in the pathobiology of DLBCL including BCL2, MYD88, CARD11, EZH2 and CREBBP (Lohr et al. 2012) and some reports suggested that the level of AID expression can be used as a marker of an unfavourable outcome for DLBCL patients who undergo cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate (Oncovin) and prednisone (CHOP)-based chemotherapy (Kawamura et al. 2015; Arima et al. 2018). The genetic landscape of the disease was further defined in a recent study, where a more comprehensive approach was used, on a large cohort of newly diagnosed patients, to describe distinct outcome-associated genetic signatures that separate patients into five-group or subsets. These distinct groups were named C1–C5 and categorized based on molecular characteristics within the two defined subtypes (Chapuy et al. 2018). The involvement of AID within these subgroups differs based on its activity and type of DNA repair mechanism that follows. Group C5 was shown to carry the most mutational burden derived from canonical AID activity (cAID) characterized by increased C > T/G mutations at the AID target RCY-motif (R = A/G, Y = C/T). This was evident in genes like BCL2 and PIM1. Additionally, the AID2 signature characterized by A > T/C/G mutations at WA (W = A/T) motifs were also identified in many recurrently mutated genes. These sites also shared properties of the COSMIC9/non-canonical AID signature, as seen in Chronic Lymphocytic Leukaemia (CLL) (Kasar et al. 2015). Furthermore, Álvarez-Prado et al. (2018) have recently identified a novel AID hotspot in B cells using capture-based deep sequencing. Genomic DNA from GC B cells was isolated from mice with BER and MMR pathway deficiency (Ung−/− Msh2−/−) or AID deficiency (Aicda−/−). They identified 275 total targets including 30 known gene targets of AID in the BER and MMR deficiency model. Subsequently, the authors interrogated the mutational hotspots within the identified set of 275 genes and reported AGCTNT as the most highly mutated AID hotspot to date. Interestingly, by analysing publicly available sequencing data for human lymphomas, 21 out of the 275 identified AID targets were also mutated, including nine novel mutated genes in DLBCL. These recent advances in lymphoma research, specifically in DLBCL, has uncovered many recurring mutations. Understanding the functional significance of these mutations in vivo would offer even more advantages in the treatment strategies of these malignancies. Aberrant demethylation plays a critical role in the pathobiology of B cell malignancies (Kretzmer et al. 2015; Oakes and Martin-Subero 2018). Tumours are known to harbour increased methylation heterogeneity compared to normal tissue. This has also been shown true for DLBCL derived cells as well as normal GC B cells likely due to the elevated expression of AICDA. Using a murine model, Teater et al (2018) showed that Aicda overexpressing mice developed a more aggressive disease and had higher levels of methylation heterogeneity correlating with increased tumour formation and decreased survival (Teater et al. 2018). Interestingly, correlation with an increased somatic mutational burden was not observed. Furthermore, in another DLBCL-related study, AID was shown to recruit Tet methylcytosine dioxygenase 2 (TET2) to the promoter of the proto-oncogene Fanconi Anaemia Complementation group A (FANCA), resulting in overexpression via demethylation, leading to increased cellular proliferation (Jiao et al. 2019).

AID in non-lymphoid cancers

Given its mutagenic physiological function in antibody diversification, it is rather unsurprising that aberrant AID activity is involved in B cell cancers. Interestingly, researchers have demonstrated AID activity in E. coli following transformation with the enzyme, illustrating that B cell-specific factors are not necessarily required (Petersen-Mahrt et al. 2002). Perhaps more unexpectedly, AID activity has also been described in various other solid tumour types. AID has been widely implicated in Inflammation-related carcinogenesis (IRC) including hepatocellular carcinomas, gastric cancers, colorectal cancer and cholangiocarcinoma (Kou et al. 2007; Matsumoto et al. 2007; Endo et al. 2008; Sawai et al. 2015). A common finding in these studies is that pro-inflammatory cytokines and/or infection can induce AID expression through the NFκB pathway. A recent example of this was shown by Araki et al. (2019), investigating the effects of inflammatory bowel disease on the development of colitis-associated cancers (CAC). They showed that IL-21 transgenic mice developed significantly larger tumours when exposed to azoxymethane (AOM) and dextran sulfate sodium (DSS) compared to their wild type counterparts. Interestingly, large intestinal epithelial cells (IECs) isolated from these transgenic mice showed greater AID mRNA levels compared to IECs isolated from wild type mice. Furthermore, treating purified IECs with IL-21 induced AID expression. These findings suggest that AID plays a role in CAC, mediated by IL-21; however, the mechanism promoting oncogenesis remains to be elucidated. In addition to exposure to Ultra Violet (UV) light, chronic inflammation has also been described as a causative agent for skin cancer, including squamous cell carcinoma, basal cell carcinoma and melanoma (Amir et al. 1992; Gloster and Neal 2006). Interestingly, mice expressing AID in the skin developed spontaneous squamous cell carcinomas with Trp53 and Hras gain of function mutations and increased levels of Cyclin D1 and epidermal growth factor receptor (EGFR) expression, culminating in the activation of the MAPK pathway. Moreover, Aicda knockdown in murine models for chemically induced skin carcinogenesis led to a decrease in tumour formation. The same study demonstrates that AID expression can be induced in human keratinocyte cell lines through inflammatory stimuli, exposure to bacterial antigen and UV irradiation (Nonaka et al. 2016).

AID is also implicated in bladder urothelial cell carcinoma (BUCC). The enzyme was shown to be upregulated in BUCC tissue and knockdown studies implicated it in invasion and metastasis, unchecked proliferation and suppressed apoptosis (Li et al. 2019). Proteomic analysis identified Matrix Metalloproteinase 14 (MMP14), an enzyme important in cancer cell invasion, to be concurrently upregulated. AID knockdown resulted in increased methylation in the MMP14 gene promoter, accompanied by decreased expression. This effect was rescued by 5-Aza-2′-deoxycytidine, an inhibitor of DNA-methylation, highlighting the importance of AID’s epigenetic contributions to BUCC. Munoz et al. (2013) investigated the contribution of AID expression during epithelial-to-mesenchymal transition (EMT) in both normal breast cells and breast cancer cells. They demonstrate that upon inflammatory stimulation with TNFα and TGF-β, AID is induced and plays a crucial role during EMT. The mechanism whereby AID accomplishes this was demonstrated through shRNA knockdown. Abrogation of AID in breast cancer cells led to a decrease in the expression of mesenchymal markers like SNAI1, SNAI2, ZEB1 and ZEB2 as well as in the expression of matrix metalloproteinases MMP2 and MMP9. Importantly, it was shown that AID regulates the expression of these EMT markers through active demethylation of CpG islands in promoter regions. Another non-lymphoid cancer type reported to involve AID activity is pancreatic cancer, whereby expression of AID along with other methylation related enzymes (TET1, TET2 and DNMT3a) correlated with increased demethylation of the MUC1 promoter, an oncogene involved in pancreatic tumour metastasis (Yokoyama et al. 2016). In Table 1 we summarize genes reported to be affected by AID’s activity and the associated cancer types.

Table 1.

Genes affected by off-target AID activity in different cancer types

Cancer type Modified genes References
Burkitt Lymphoma C-MYC, ID3 Ramiro et al. (2004); Duquette et al. (2005); Robbiani et al. (2008); Richter et al. (2012)
Diffuse Large B Cell Lymphoma BCL2, MYD88, CARD11, EZH2, CREBBP, PIM1, FANCA Lohr et al. (2012); Chapuy et al. (2018); Jiao et al. (2019)
Breast Cancer SNAI1, SNAI2, ZEB1, ZEB2, MMP2 MMP9 Munoz et al. (2013)
Squamous Cell Carcinoma Trp53, Hras Nonaka et al. (2016)
Pancreatic Cancer MUC1 Yokoyama et al. (2016)
Bladder urothelial carcinoma MMP14 Li et al. (2019)
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Conclusion

AID is an essential enzyme of the adaptive immune system which, under normal conditions, enables antibody affinity and specificity diversification. However, AID is also associated with a range of pathological conditions (summarized in Table 2).

Table 2.

Summary of the physiological and pathological activities of AID with select references

Physiological involvement of AID References Pathological Involvement of AID References
Somatic hypermutation and Class switch recombination Muramatsu et al. (2000); Petersen-Mahrt et al. (2002) c-MYC/IGH translocation in BL Ramiro et al. (2004); Robbiani et al. (2008); Takizawa et al. (2008)
DNA demethylation during B-cell maturation Dominguez et al. (2015) Deregulation by EBV in lymphomas Epeldegui et al. (2007a, b); Heath et al. (2012); Kim et al. (2013); Kalchschmidt et al. (2016); Grande et al. (2019)
Cell reprogramming (oocyte and pluripotent stem cells) Morgan et al. (2004); Rai et al. (2008); Popp et al. (2010) Malaria driven deregulation in eBL Torgbor et al. (2014); Robbiani et al. (2015)
HIV-associated NHL through deregulation by HIV proteins Wang et al. 2018; Sall et al. (2019)
Gene deregulation in DLBCL Lohr et al. (2012); Álvarez-Prado et al. (2018); Chapuy et al. (2018)
Methylation heterogeneity in DLBCL Teater et al. (2018)
Involvement in inflammation related cancers Munoz et al. (2013); Nonaka et al. (2016); Li et al. (2019)
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Under these pathophysiological conditions AID can become deregulated, leading to off-target mutational and epigenetic changes to DNA, affecting the expression and activity of both tumour promoters and tumour suppressors. This has been described for both B-cell lymphomas, as well as several non-lymphoid cancers (Fig. 1a, b). Notably, strong evidence now exists showing direct action of pathogenic agents including EBV, P. falciparum and HIV in deregulating the transcriptional control of AICDA expression. More research aimed at elucidating the role of AID in cancer is needed, particularly relating to its epigenetic role in promoting gene deregulation and oncogenesis. While there are currently no molecules identified as specific inhibitors of AID which could be used in clinical trials, inhibitors of HSP90, its stabilizing partner, show promise in various phases of clinical trials, but with certain drawbacks (Talaei et al. 2019). The identification of a specific AID inhibitor, and the use of AID as a target for therapy or as a predictive marker for disease prognosis could be important in improving cancer treatment and monitoring.

Fig.1.

Fig.1

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Illustration of AID deregulation, affected downstream genes and cellular consequences in lymphoid and non-lymphoid cancers. a AID dysregulation by pathogenic agents leads to off-target mutations in key oncogenes/ tumour suppressors inhibiting apoptosis and promoting proliferation, culminating in mature B cell lymphomas. b AID dysregulation by UV irradiation, pathogenic infection and chronic inflammation leads to off-target mutations in genes involved in EMT and proliferation, ultimately leading to the development of carcinomas

Acknowledgements

Philipe Alves de Souza Rios for assisting in developing the graphics in Fig. 1.

Abbreviations

A-EJ

Alternative end-joining

AID

Activation induced cytidine deaminase

AIDS

Acquired immune deficiency disorder

AOM

Azoxymethane

APE1

Apyrimidinic endonuclease

APOBEC

Apolipoprotein B mRNA editing catalytic polypeptide-like

ATP

Adenosine triphosphate

BER

Base excision repair

BL

Burkitt lymphoma

BUCC

Bladder urothelial cell carcinoma

CAC

Colitis-associated cancers

CHOP

Cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisone

CRM-1

Chromosome maintenance 1

CSR

Class switch recombination

dC

Deoxycytidine

DLBCL

Diffuse large B cell lymphoma

DSS

Dextran sulfate sodium

dU

Deoxyuridine

EBNA2

Epstein-Barr virus nuclear antigen 2

EBNA3C

Epstein-Barr virus nuclear antigen 3C

EBV

Epstein-Barr virus

EGFR

Epidermal growth factor receptor

EMT

Epithelial-to-mesenchymal transition

GC

Germinal centre

HAART

Highly active antiretroviral therapy

HIV

Human immunodeficiency virus

IECs

Intestinal epithelial cells

IRC

Inflammation-related carcinogenesis

LMP1

Latent Membrane Protein 1

MMP14

Matrix Metalloproteinase 14

MMR

Mismatch repair

NES

Nuclear export signal

NHEJ

Non-homologous end-joining

NHL

Non-Hodgkin lymphomas

NLS

Nuclear localisation signal

PD-L1

Programmed Cell Death Ligand

RBPJ

Recombination binding protein

REG-γ

REGgamma

SHM

Somatic hypermutation

ssDNA

Single stranded DNA

TLR9

Toll-like receptor 9

TSS

Transcription start site

UNG

Uracil-DNA glycosylase

UV

Ultraviolet

Funding

Not applicable.

Code availability

Not applicable.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethics approval

Not applicable.

Consent to participate:

Not applicable.

Consent for publication

All authors have consented to the publication of this manuscript.

Availability of data and material

Data sharing does not apply to this article as no datasets were generated or analysed during the current study.

Footnotes

Publisher's Note

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