APOBEC3B, a molecular driver of mutagenesis in human cancers

Zou, Jun; Wang, Chen; Ma, Xiangyi; Wang, Edward; Peng, Guang

doi:10.1186/s13578-017-0156-4

Cited by 70 publications

(69 citation statements)

References 87 publications

(119 reference statements)

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“…This TET-type dependent pathway likely carries out the bulk of the demethylations discussed here. However, as reviewed [25], two other pathways involving AID/APOBEC and base excision repair enzymes can occur. In one pathway there is an initial TET reaction.…”

Section: Mechanisms Of Demethylationmentioning

confidence: 99%

Demethylation in Early Embryonic Development and Memory

Bernstein¹,

Bernstein²

2020

DNA Methylation Mechanism

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DNA repair processes arose early in evolution. During evolution, DNA base excision repair apparently acquired additional roles in demethylation of cytosines in DNA. Demethylation is central to two mammalian fundamental processes. Embryonic reprogramming and neuronal memory require rapid gene expression alterations depending in part on demethylations. The active demethylation reactions in both processes primarily depend, first, on the family of 5-methylcytosine oxidases sharing the acronym ten-eleven translocation (TET methylcytosine dioxygenases) and, second, on DNA base excision repair enzymes. In mice, within 6 h of fertilization, the paternal chromosomes are close to 100% actively demethylated through TET and repair activity. (Methylation of maternal DNA is blocked during subsequent cycles of replication, so methyl groups on maternal DNA, passively, becomes highly diluted over the next 4 days.) Rats subjected to one instance of contextual fear conditioning create an especially strong long-term memory. At 24 h after training, 9.2% of the genes in the rat genomes of hippocampus neurons are differentially methylated, including over 500 genes with demethylation. The emergence of embryonic development in evolution depended on preexisting DNA methylation/demethylation pathways to modify gene expression. The further emergence of memory likely evolved from the earlier set of methylation/demethylation capabilities associated with embryonic development.

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Section: Mechanisms Of Demethylationmentioning

confidence: 99%

Demethylation in Early Embryonic Development and Memory

Bernstein¹,

Bernstein²

2020

DNA Methylation Mechanism

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“…A3 proteins are currently considered predominant mutagenic agents having effects on the genesis and evolution of various cancers . This so‐called “DNA mutator hypothesis” was initially formulated based on two observations: the overexpression of several A3 family members in cancer cell lines and primary tumor samples and the presence of the A3‐signature mutations (substitutions of C with T or G in TCA or TCT motifs) in many different human tumors.…”

Section: Increased A3b Expression and Mutation Signature In Human Canmentioning

confidence: 99%

“…A3 proteins are currently considered predominant mutagenic agents having effects on the genesis and evolution of various cancers. 59,60 This so-called "DNA mutator hypothesis" was initially formulated The table summarizes the main signaling pathways of A3A and A3B (dys)regulation described in cancer cell lines. Abbreviations: ATR, Rad3-related serine/threonine kinase; Chk1, checkpoint kinase 1; n.d., not determined; NF-kB, nuclear factor kappa B; Tag, large T antigen; TEAD, TEA domain DNA-binding factor; ZNF384, zinc finger protein 384.…”

Section: Increased A3b Expression and Mutation Signature In Human Canmentioning

confidence: 99%

Understanding the regulation of APOBEC3 expression: Current evidence and much to learn

Covino

Gauzzi

Fantuzzi

2017

Journal of Leukocyte Biology

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The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) family of cytosine deaminases plays crucial roles in innate immunity through the ability of restricting viral replication by deamination and mutation of viral genomes. The antiviral function of these proteins was first discovered when research in the field of HIV infection revealed that one member of the family, namely APOBEC3G, restricts HIV infection in T lymphocytes and that the viral infectivity factor protein drives the proteosomal degradation of this enzyme, thus overriding its antiviral function. Recent advances in cancer genomics, together with biochemical characterization of the APOBEC3 enzymes, have now implicated some family members in somatic mutagenesis during carcinogenesis. While several studies investigated the downstream consequences of APOBEC3 expression and activity, either in the context of viral infection or tumorigenesis, little is known on the upstream mechanisms regulating APOBEC3 expression. Such knowledge would be of huge importance in developing innovative approaches to strengthen antiviral innate immunity on one side and to prevent cancer development on the other. This mini review summarizes research advances on the molecular mechanisms regulating the expression of APOBEC3 family members in selected immune cell populations and cancer cells.

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“…[5][6][7][8][9] A3 proteins have specific substrate sequence preferences, and analyses of some cancer genomes have shown an enrichment of A3 mutation signatures. [10][11][12][13][14][15] Recent evidence suggests that APOBEC3B (A3B) is an important driver of tumor progression in the A3 family. 16,17 A3B is a dual domain A3 that prefers to deaminate cytosines at T C motifs in DNA, with weak preference placed on further upstream and downstream bases.…”

Section: Introductionmentioning

confidence: 99%

“…5-9 A3 proteins have specific substrate sequence preferences, and analyses of some cancer genomes have shown an enrichment of A3 mutation signatures. [10][11][12][13][14][15] Recent evidence suggests that APOBEC3B (A3B) is an important driver of tumor progression in the A3 family. 16,17 …”

mentioning

confidence: 99%

Determinants of Substrate Specificity in APOBEC3B

Wagner

Demir²,

Carpenter³

et al. 2018

Preprint

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APOBEC3B (A3B) is a newly discovered driver of mutation in many cancers. We use computational tools to revert a recent crystal structure of an A3B construct to its native sequence, and run molecular dynamics simulations to study its underlying dynamics and substrate recognition mechanisms. The A3B oligonucleotide substrate simulations show a series of dynamic substrate protein contacts that correlate with previous work on A3B substrate selectivity. A second series of simulations in which the target cytosine nucleotide was computationally mutated from a deoxyribose to a ribose showed a change in sugar ring pucker, leading to a rearrangement of the binding site and revealing a potential intermediate in the binding pathway. Finally, apo simulations of A3B beginning in the open state experience a rapid and consistent closure of the binding site, reaching a conformation incompatible with substrate binding. These simulations agree with previous experimental studies, and we report the atomistic details of these events to further therapeutic studies on A3B. IntroductionThe APOBEC3 (A3) family of cytidine deaminases is a recently discovered endogenous source of mutation in cancer. 1,2 Previously, A3 proteins were studied in the context of their interactions with viruses and efforts were undertaken to discover small molecules that modulate the mutational activities of the virally restrictive APOBEC3G enzyme. 3,4 Recent studies have linked cancer progression and recurrence to A3 activity. 5-9 A3 proteins have specific substrate sequence preferences, and analyses of some cancer genomes have shown an enrichment of A3 mutation signatures. [10][11][12][13][14][15] Recent evidence suggests that APOBEC3B (A3B) is an important driver of tumor progression in the A3 family. 16,17

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APOBEC3B, a molecular driver of mutagenesis in human cancers

Cited by 70 publications

References 87 publications

Demethylation in Early Embryonic Development and Memory

Demethylation in Early Embryonic Development and Memory

Understanding the regulation of APOBEC3 expression: Current evidence and much to learn

Determinants of Substrate Specificity in APOBEC3B

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