APOBEC3B can impair genomic stability by inducing base substitutions in genomic DNA in human cells

Shinohara, Masanobu; Io, Katsuhiro; Shindo, Keisuke; Matsui, Masashi; Sakamoto, Takashi; Tada, Kohei; Kobayashi, Masayuki; Kadowaki, Norimitsu; Takaori‐Kondo, Akifumi

doi:10.1038/srep00806

Cited by 95 publications

(105 citation statements)

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“…This is considered to be due to an increased transition from dC to dT and the resultant increased mutation frequency (5). These mutations were commonly found in oncogenes transcribed in tumor cells (17); for example, in lymphoma cell lines, overexpression of APOBEC3B produced an increase in dC to dT mutations in c-Myc (18). In the present study, it was shown that APOBEC3B was present in all of the fetal leptomeninges, 88% of WHO grade I, 100% of grade II and 83% of grade III meningiomas tested, without differences between grades.…”

Section: Discussionsupporting

confidence: 46%

APOBEC3B expression in human leptomeninges and meningiomas

2016

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Abstract. Nucleic acid-editing enzymes of the apolipoprotein B mRNA-editing enzyme (APOBEC) family have been associated with somatic mutation in cancer. However, the role of APOBEC catalytic subunit 3B (APOBEC3B) editing in the pathogenesis of base substitutions in meningiomas is unknown. In the present study, the expression of APOBEC3B was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analyses in five fetal and one adult human leptomeninges and 38 meningiomas. Genomic DNA was sequenced using the Illumina Tru-Seq Cancer Panel. Three meningioma primary cultures were also established and treated with cerebrospinal fluid form patients without neurological disease or platelet-derived growth factor-BB (PDGF-BB), prior to evaluation of APOBEC3B expression. By western blotting, APOBEC3B was revealed to be present in 100% of the fetal leptomeninges, and in 88% of World Health Organization grade I, 100% of grade II and 83% of grade III meningiomas tested, but was not different between grades. RT-qPCR revealed no difference in the mRNA expression of APOBEC3B between grades. Sequencing revealed no elevated levels of the C>T mutations that are characteristic of APOBEC3B editing of genomic DNA. Treatment with cerebrospinal fluid and PDGF-BB had no effect on APOBEC3B protein expression in the leptomeningeal or meningioma cells. These findings suggest that the mutations associated with increased APOBEC3B expression may not be central to the pathogenesis of meningiomas. IntroductionRecent studies have indicated that normal cellular enzymatic activity may contribute to the genomic changes associated with various neoplasias (1-3). Apolipoprotein B mRNA-editing enzymes (APOBEC) comprise a family of enzymes that protect immune function and are involved in mRNA editing; their cytosine deaminase activity may also induce base substitutions in the genomes of malignancies (1,2).APOBEC3B is a cytosine deaminase that is responsible for the deamination of cytosines in the genome of host cells, producing cytosine to thymidine mutations (2). Recently studies have found that APOBEC3B is overexpressed in several types of malignancy, resulting in clusters of C>T mutations that are considered to be the signature of APOBEC mutation in tumors. Analysis of whole-genome and whole-exome sequencing data from various types of malignancy have implicated APOBEC members in mRNA editing and the production of cytosine mutation clusters in the development or progression of numerous neoplastic processes, encompassing lung, breast, hepatic and hematopoietic malignancies (4-9). APOBEC3B overexpression has been identified in breast, head and neck cancers (7-10). Although APOBEC3B expression has not been studied in meningiomas, the presence of C>T point mutations in some meningioma cases raises the possibility that APOBEC3B may participate in the pathogenesis of at least a subset of meningiomas (11).The present study evaluated APOBEC3B expression in addition to mutations in a series of normal leptomeninges, an...

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Section: Discussionsupporting

confidence: 46%

APOBEC3B expression in human leptomeninges and meningiomas

2016

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“…Other AID/APOBECs have been shown to induce DNA damage and somatic mutations [30,54,55], and they are involved in kataegis, clusters of mutations observed in some cancer genomes [29,32,35,56,57]. An AID/APOBEC mutational signature can be observed in genes highly mutated in cancer [39] and in cancer genomes and exomes [31,[33][34][35]58].…”

Section: Aid/apobec Mutational Signature In Esophageal Adenocarcinomasmentioning

confidence: 99%

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

et al. 2014

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Background: The AID/APOBECs are deaminases that act on cytosines in a diverse set of pathways and some of them have been linked to the onset of genetic alterations in cancer. Among them, APOBEC1 is the only family member to physiologically target RNA, as the catalytic subunit in the Apolipoprotein B mRNA editing complex. APOBEC1 has been linked to cancer development in mice but its oncogenic mechanisms are not yet well understood. Results: We analyze whether expression of APOBEC1 induces a mutator phenotype in vertebrate cells, likely through direct targeting of genomic DNA. We show its ability to increase the inactivation of a stably inserted reporter gene in a chicken cell line that lacks any other AID/APOBEC proteins, and to increase the number of imatinib-resistant clones in a human cellular model for chronic myeloid leukemia through induction of mutations in the BCR-ABL1 fusion gene. Moreover, we find the presence of an AID/APOBEC mutational signature in esophageal adenocarcinomas, a type of tumor where APOBEC1 is expressed, that mimics the one preferred by APOBEC1 in vitro.

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“…However, A3A has also been shown to be genotoxic under conditions of overexpression (22,23,26) and to mutate genomic DNA (24,25). CD14 ϩ cells are known to express high levels of A3A upon type I IFN induction (4,6,7), suggesting that these cells must either have a mechanism for regulating A3A activity or be subject to its genotoxic effects.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpressed A3A has been shown to cause chromosomal DNA damage and mutation (22)(23)(24)(25)(26) as well as disruption of the cell cycle (22,26). Expression of A3A in a cell threatens genomic integrity, suggesting that uncontrolled activation of this immune defense molecule would have undesirable consequences.…”

mentioning

confidence: 99%

Endogenous APOBEC3A DNA Cytosine Deaminase Is Cytoplasmic and Nongenotoxic

Land

Law

Carpenter

et al. 2013

Journal of Biological Chemistry

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Background: APOBEC3A is a potentially genotoxic DNA cytosine deaminase expressed in myeloid lineage cells. Results: Exogenous APOBEC3A genotoxicity correlates with expression level and nuclear localization. Endogenous APOBEC3A is nontoxic and cytoplasmic, despite its capacity to be highly induced by interferon. Conclusion: Cytoplasmic localization prevents endogenous APOBEC3A from accessing nuclear DNA. Significance: Endogenous APOBEC3A is not genotoxic.

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APOBEC3B can impair genomic stability by inducing base substitutions in genomic DNA in human cells

Cited by 95 publications

References 50 publications

APOBEC3B expression in human leptomeninges and meningiomas

APOBEC3B expression in human leptomeninges and meningiomas

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

Endogenous APOBEC3A DNA Cytosine Deaminase Is Cytoplasmic and Nongenotoxic

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