Nucleotide Weight Matrices Reveal Ubiquitous Mutational Footprints of AID/APOBEC Deaminases in Human Cancer Genomes

Rogozin, Igor B.; Roche-Lima, Abiel; Lada, Artem G.; Belinky, Frida; Sidorenko, I. A.; Glazko, Galina V.; Babenko, Vladimir N.; Cooper, David Neil; Pavlov, Youri I.

doi:10.3390/cancers11020211

Cited by 15 publications

(21 citation statements)

References 57 publications

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“…APOBEC1 and several of the closely related A3 enzymes (A3A, B, C, D, F and H) display a preference for deamination of TpC sites in ssDNA in vitro that is consistent with the TpC mutational signatures observed in cancer genomes, with gene expression analysis and loss-of-function experiments in breast cancer cell lines suggesting a prominent role for A3B (Burns et al 2013a). Distinct A3G and AID mutational signatures have also been detected across a wide range of cancer types (Rogozin et al 2019) but for the purposes of this review, we focus on the TpC signatures, henceforth referred to as APOBEC associated. Analyses of cancer genome sequencing data and studies in cells overexpressing A3A or A3B suggest the major exposure of ssDNA substrate for A3 activity in tumour cells arises on the lagging strand during DNA replication, presumably as a result of replication fork stalling due to replication stress (Green et al 2016, Haradhvala et al 2016, Hoopes et al 2016, Morganella et al 2016, Seplyarskiy et al 2016.…”

Section: The A3 Genes and Somatic Mutagenesis In Cancersupporting

confidence: 64%

The APOBEC3 genes and their role in cancer: insights from human papillomavirus

Smith

Fenton

2019

Journal of Molecular Endocrinology

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The interaction between human papillomaviruses (HPV) and the apolipoprotein-B mRNA-editing catalytic polypeptide-like (APOBEC)3 (A3) genes has garnered increasing attention in recent years, with considerable efforts focused on understanding their apparent roles in both viral editing and in HPV-driven carcinogenesis. Here, we review these developments and highlight several outstanding questions in the field. We consider whether editing of the virus and mutagenesis of the host are linked or whether both are essentially separate events, coincidentally mediated by a common or distinct A3 enzymes. We discuss the viral mechanisms and cellular signalling pathways implicated in A3 induction in virally infected cells and examine which of the A3 enzymes might play the major role in HPV-associated carcinogenesis and in the development of therapeutic resistance. We consider the parallels between A3 induction in HPV-infected cells and what might be causing aberrant A3 activity in HPV-independent cancers such as those arising in the bladder, lung and breast. Finally, we discuss the implications of ongoing A3 activity in tumours under treatment and the therapeutic opportunities that this may present.

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Section: The A3 Genes and Somatic Mutagenesis In Cancersupporting

confidence: 64%

The APOBEC3 genes and their role in cancer: insights from human papillomavirus

Smith

Fenton

2019

Journal of Molecular Endocrinology

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“…Detection of driver mutations in nucleotide sequences is helped by exploiting mutational signatures that are based on distinct genomic footprints. Footprints can be defined by nucleotide substitution patterns [39,40], localized mutation densities, and patterns of genomic structural variation [40][41][42][43]. These can include The figure depicts the theoretical basis to understand the concepts discussed in this work.…”

Section: Driver Mutations and Frequent Passenger Mutationsmentioning

confidence: 99%

Why Are Some Driver Mutations Rare?

Nussinov

Tsai

Jang

2019

Trends in Pharmacological Sciences

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Understanding why driver mutations that promote cancer are sometimes rare is important for precision medicine since it would help in their identification. Driver mutations are largely discovered through their frequencies. Thus, rare mutations often escape detection. Unlike high-frequency drivers, low-frequency drivers can be tissue specific; rare drivers have extremely low frequencies. Here, we discuss rare drivers and strategies to discover them. We suggest that allosteric driver mutations shift the protein ensemble from the inactive to the active state. Rare allosteric drivers are statistically rare since, to switch the protein functional state, they cooperate with additional mutations, and these are not considered in the patient cancer-specific protein sequence analysis. A complete landscape of mutations that drive cancer will reveal tumorspecific therapeutic vulnerabilities. Mutations That Drive Cancer Can Be Frequent or RareHere we ask: Why are some driver mutations rare? Both frequent and rare drivers bestow a selective advantage to a clone in its microenvironment by promoting cell survival and proliferation; thus why are driver mutations sometimes rare? This question is important. If understood, it would help not only in uncovering the mechanisms of driver mutations, but also their identification and drug discovery. Yet, to date it has not been asked.Precision medicine efforts to uncover actionable mutations that drive cancer in patients have galvanized big-data initiatives. They have spurred development of experimental approaches to accumulate data [e.g., The Cancer Genome Atlas (TCGA) [1], Cancer Genome Project (CGP) [2], and Catalogue of Somatic Mutations in Cancer (COSMIC) [3]], and prompted the formation of the International Cancer Genome Consortium [4,5], and advances in computational algorithms to search and analyze it [6][7][8][9][10][11][12][13]. The outcome witnessed an increase in experimental and efficient computational methods, analyses tools and applications, servers, and reviews [5][6][7][8][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. At the same time, they have also shown that the state-of-the-art computational strategies that integrate and prioritize the data [30,31] have been unsuccessful in predicting all clinically diagnosed cancer drivers. This implies some deficiencies, not necessarily of the software itself, but its underlying conceptual biological basis. Among the emerging flaws have been the unidentified, yet clinically diagnosed, rare driver mutations. This raised the challenging question of how to identify rare driver mutations [8,[32][33][34]. Driver mutations contribute to cancer development. They can be statistically frequent or rare, at the tail of the distribution, as are passenger mutations that do not promote cancer [35]. Rare drivers are likely to be in oncogenes or tumor suppressors and are present in <1% of cancers. If direct functional or signaling data are unavailable, which is often the case, how then can we distinguish between rare driver and pa...

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“…A strong association between human APOBEC1 expression and the APOBEC mutational signature was found in esophageal adenocarcinomas [78] and APOBEC1 expression was also correlated with indel mutations in many tumor genomes [79]. Moreover, a fine analysis of mutational footprints was able to extract a specific APOBEC1 mutational motif that can be found in many human cancer genomes [80]. Similarly, although rabbit A1 was found inactive on nuclear DNA in our experimental setup, over-expression of rabbit A1 in transgenic animals results in hepatocellular carcinoma [58], suggesting that the enzyme may under some conditions contribute to tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA

et al. 2019

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BackgroundAPOBEC1 (A1) enzymes are cytidine deaminases involved in RNA editing. In addition to this activity, a few A1 enzymes have been shown to be active on single stranded DNA. As two human ssDNA cytidine deaminases APOBEC3A (A3A), APOBEC3B (A3B) and related enzymes across the spectrum of placental mammals have been shown to introduce somatic mutations into nuclear DNA of cancer genomes, we explored the mutagenic threat of A1 cytidine deaminases to chromosomal DNA.ResultsMolecular cloning and expression of various A1 enzymes reveal that the cow, pig, dog, rabbit and mouse A1 have an intracellular ssDNA substrate specificity. However, among all the enzymes studied, mouse A1 appears to be singular, being able to introduce somatic mutations into nuclear DNA with a clear 5’TpC editing context, and to deaminate 5-methylcytidine substituted DNA which are characteristic features of the cancer related mammalian A3A and A3B enzymes. However, mouse A1 activity fails to elicit formation of double stranded DNA breaks, suggesting that mouse A1 possess an attenuated nuclear DNA mutator phenotype reminiscent of human A3B.ConclusionsAt an experimental level mouse APOBEC1 is remarkable among 12 mammalian A1 enzymes in that it represents a source of somatic mutations in mouse genome, potentially fueling oncogenesis. While the order Rodentia is bereft of A3A and A3B like enzymes it seems that APOBEC1 may well substitute for it, albeit remaining much less active. This modifies the paradigm that APOBEC3 and AID enzymes are the sole endogenous mutator enzymes giving rise to off-target editing of mammalian genomes.

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Nucleotide Weight Matrices Reveal Ubiquitous Mutational Footprints of AID/APOBEC Deaminases in Human Cancer Genomes

Cited by 15 publications

References 57 publications

The APOBEC3 genes and their role in cancer: insights from human papillomavirus

The APOBEC3 genes and their role in cancer: insights from human papillomavirus

Why Are Some Driver Mutations Rare?

Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA

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