The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas

Saraconi, Giulia; Severi, Francesco; Sala, Cesare; Mattiuz, Giorgio; Conticello, Silvestro G.

doi:10.1186/preaccept-3516273912883547

Cited by 46 publications

(65 citation statements)

References 61 publications

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“…While rabbit APOBEC1 clearly has a dramatic carcinogenic effect when expressed constitutively in transgenic mice, this was not the case when expressed in rabbits [38] and it has not yet proven relevant to human cancers (although a recent study has implicated APOBEC1 in esophageal adenocarcinomas). [39] It should also be noted that this original APOBEC1 study [38] was performed prior to the discovery of AID/APOBEC catalyzed DNA cytosine deamination, [17,40] and therefore, the authors inferred that off-target RNA editing caused the observed malignancies.…”

Section: Previously Implicated Apobecsmentioning

confidence: 99%

APOBEC3B: Pathological consequences of an innate immune DNA mutator

Burns¹,

Leonard²,

Harris³

2015

Biomed J

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Cancer is a disease that results from alterations in the cellular genome. Several recent studies have identified mutational signatures that implicate a variety of mutagenic processes in cancer, a major one of which is explained by the enzymatic activity of the DNA cytosine deaminase, APOBEC3B. As a deaminase, APOBEC3B converts cytosines to uracils in single-stranded DNA. Failure to properly repair these uracil lesions can result in a diverse array of mutations. For instance, DNA uracils can template the insertion of complementary adenines leading to C-to-T transition mutations. DNA uracils can also be converted into abasic sites that, depending upon the DNA polymerase recruited to bypass this lesion in the template strand, can lead to adenine insertion and C-to-T mutations as well as cytosine insertion and C-to-G transversion mutations. Finally, DNA uracils can also be converted into DNA breaks that may precipitate some types of larger chromosomal aberrations observed in cancer. These studies cumulatively demonstrate that APOBEC3B is a major source of genetic heterogeneity in several human cancers and, as such, this enzyme may prove to be a critical diagnostic and therapeutic target. (Biomed J 2015;38:102-110)

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Section: Previously Implicated Apobecsmentioning

confidence: 99%

APOBEC3B: Pathological consequences of an innate immune DNA mutator

Burns¹,

Leonard²,

Harris³

2015

Biomed J

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“…Overexpression of APOBEC1, APOBEC3A, and APOBEC3B is associated with increased mutation rate in vertebrate cell lines, with mutations distributed all over the genome (Saraconi et al 2014;Akre et al 2016;Green et al 2016). Notably, however, APOBEC1 causes C→A mutations in experimental systems (Saraconi et al 2014), while the heritable replication asymmetry is largely restricted to C→T and C→G mutations (Table 1). Recently, one of the alleles of APOBEC3H has been linked with lung cancer , suggesting this protein as another possible candidate.…”

Section: Apobec3a And/or Apobec3b Proteins Are Most Plausible Causes mentioning

confidence: 99%

“…While deamination in the TpCpW context excludes some APOBECs from consideration, APOBEC1, APOBEC3A, APOBEC3B, APOBEC3F, and APOBEC3H (Taylor et al 2013;Kim et al 2014;Saraconi et al 2014) all are plausible suspects. Overexpression of APOBEC1, APOBEC3A, and APOBEC3B is associated with increased mutation rate in vertebrate cell lines, with mutations distributed all over the genome (Saraconi et al 2014;Akre et al 2016;Green et al 2016). Notably, however, APOBEC1 causes C→A mutations in experimental systems (Saraconi et al 2014), while the heritable replication asymmetry is largely restricted to C→T and C→G mutations (Table 1).…”

Section: Apobec3a And/or Apobec3b Proteins Are Most Plausible Causes mentioning

confidence: 99%

APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context

2016

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APOBEC3A/B cytidine deaminase is responsible for the majority of cancerous mutations in a large fraction of cancer samples. However, its role in heritable mutagenesis remains very poorly understood. Recent studies have demonstrated that both in yeast and in human cancerous cells, most APOBEC3A/B-induced mutations occur on the lagging strand during replication and on the nontemplate strand of transcribed regions. Here, we use data on rare human polymorphisms, interspecies divergence, and de novo mutations to study germline mutagenesis and to analyze mutations at nucleotide contexts prone to attack by APOBEC3A/B. We show that such mutations occur preferentially on the lagging strand and on nontemplate strands of transcribed regions. Moreover, we demonstrate that APOBEC3A/B-like mutations tend to produce strandcoordinated clusters, which are also biased toward the lagging strand. Finally, we show that the mutation rate is increased 3 ′ of C→G mutations to a greater extent than 3 ′ of C→T mutations, suggesting pervasive trans-lesion bypass of the APOBEC3A/B-induced damage. Our study demonstrates that 20% of C→T and C→G mutations in the TpCpW context-where W denotes A or T, segregating as polymorphisms in human population-or 1.4% of all heritable mutations are attributable to APOBEC3A/B activity.

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“…The human and rat APOBEC1 expression vectors described in Saraconi et al 15 were digested with BglII/BsrGI to remove the IRES-EGFP sequence and ligated back after blunting the DNA ends. The APOBEC-1DC construct was obtained by PCR with primers 7 and 8 and cloned back into the pAIDexpressPuro2 backbone.…”

Section: Plasmidsmentioning

confidence: 99%

“…2,11,12 Moreover, its ability to target DNA has been linked to mutagenesis and human cancer. [13][14][15] Higher expression levels of APOBEC1 induce hyperediting of physiological RNA targets at additional sites, as well as of other genes. e.g.…”

Section: Introductionmentioning

confidence: 99%

Flow-cytometric visualization of C>U mRNA editing reveals the dynamics of the process in live cells

Severi

Conticello

2015

RNA Biology

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APOBEC1 is the catalytic subunit of the complex that edits ApolipoproteinB (ApoB) mRNA, which specifically deaminates cytidine 6666 to uracil in the human transcript. The editing leads to the generation of a stop codon, resulting in the synthesis of a truncated form of ApoB. We have developed a method to quantitatively assay ApoB RNA editing in live cells by using a double fluorescent mCherry-EGFP chimera containing a »300bp fragment encompassing the region of ApoB subject to RNA editing. Coexpression of APOBEC1 together with this chimera causes specific RNA editing of the ApoB fragment. The insertion of a stop codon between the mCherry and EGFP thus induces the loss of EGFP fluorescence. Using this method we analyze the dynamics of APOBEC1-dependent RNA editing under various conditions. Namely we show the interplay of APOBEC1 with known interactors (ACF, hnRNP-C1, GRY-RBP) in cells that are RNA editing-proficient (HuH-7) or -deficient (HEK-293T), and the effects of restricted cellular localization of APOBEC1 on the efficiency of the editing. Furthermore, our approach is effective in assaying the induction of RNA editing in Caco-2, a cellular model physiologically capable of ApoB RNA editing.

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The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas

Cited by 46 publications

References 61 publications

APOBEC3B: Pathological consequences of an innate immune DNA mutator

APOBEC3B: Pathological consequences of an innate immune DNA mutator

APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context

Flow-cytometric visualization of C>U mRNA editing reveals the dynamics of the process in live cells

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