AID/APOBEC deaminases and cancer

Abstract

Mutations are the basis for evolution and the development of genetic diseases. Especially in cancer, somatic mutations in oncogenes and tumor suppressor genes alongside the occurrence of passenger mutations have been observed by recent deep-sequencing approaches. While mutations have long been considered random events induced by DNA-replication errors or by DNA damaging agents, genome sequencing led to the discovery of non-random mutation signatures in many human cancer. Common non-random mutations comprise DNA strand-biased mutation showers and mutations restricted to certain DNA motifs, which recently have become attributed to the activity of the AID/APOBEC family of DNA deaminases. Hence, APOBEC enzymes, which have evolved as key players in natural and adaptive immunity, have been proposed to contribute to cancer development and clonal evolution of cancer by inducing collateral genomic damage due to their DNA deaminating activity. This review focuses on how mutagenic events through AID/APOBEC deaminases may contribute to cancer development.

Activation induced deaminase mutational signature overlaps with CpG methylation sites in follicular lymphoma and other cancers

“…Recently, this methodology has become popular in the analysis of cancer genomes311. As predicted after the discovery of DNA editing by AID and APOBEC cytosine deaminases12, mutations in DNA sequence contexts similar to mutations induced by deaminases in model systems have been found in several types of cancer231314. Studies of mutations induced by deaminases are facilitated by their unique properties, namely, the ability to produce, in vitro , clustered mutations in ssDNA at specific contexts surrounding cytosines81516 and retention of the signatures of deaminase-induced mutagenesis and propensity for clustered mutations, kataegis in vivo , in heterologous models where no potential specific cofactors are expected to be present17181920212223.…”

Cancer Risks Linked to the Bad Luck Hypothesis and Epigenomic Mutational Signatures

“…More than 30 distinct mutational signatures across 36 cancer types were found to contribute to cancer phenotypes [35,36,51]. They are available in the COSMIC database and are shown in Figure 2.…”

“…They are available in the COSMIC database and are shown in Figure 2. The APOBEC-associated signature is the second most common, and is likely involved in somatic mutagenesis in the lagging single DNA strand, as compared with the leading strand, during the process of DNA replication [35,36,51]. It is remarkable that APOBEC proteins are also involved in anti-virus defense, as well as genomic surveillance of the retro-transposition of the endogenous long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs) and long terminal repeat (LTR) retrotransposons [52,53].…”

“…The most common mutational signatures observed in many types of cancer are associated with MMR and HR deficiencies or upregulation of cytosine deaminase enzymes known as APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family enzymes (APOBEC1, APOBEC2, and APOBEC3A-H), which display various physiological functions. APOBECs cause hypermutation, termed "kataegis", which usually occurs exclusively in regions with dC>dT transitions at TpC dinucleotides [35]. The HR-deficiency signature is commonly observed in breast, ovarian and pancreatic tumors.…”

Structural and functional assessment of APOBEC3G macromolecular complexes

“…APOBECs as they are expressed in mammalian cells either have little or no deaminase activity (APOBEC 2 and 4) [5, 6], only edit RNA (A1) [7–9], only deaminate single-stranded (ssDNA) (Activation Induced Deaminase (AID), A3B, 3D, 3F, 3G and 3H) [10–16] or deaminate both RNA and ssDNA (APOBEC3A) [17, 18]. Identification of these proteins has led to new understandings of how APOBECs are involved in genomic evolution and genetic stability [19–22], cancer [9, 23–28], control of retrotransposition [13, 29–35], class switch recombination and somatic hypermutation of the IgG locus for acquired immunity [36–39] and anti-retroviral activity [11, 15, 22, 27, 37, 40, 41]. Many of the functions of APOBECs rely on protein-protein and protein-nucleic acids interactions and in some instances post-translational modifications, to regulate their subcellular compartmentalization, substrate specificity and biological activity (reviewed in [1, 42]).…”