APOBEC3 genes: retroviral restriction factors to cancer drivers

Henderson, Stephen; Fenton, Tim R.

doi:10.1016/j.molmed.2015.02.007

Cited by 106 publications

(98 citation statements)

References 89 publications

(146 reference statements)

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“…13,17,18 Here we report that A3A expression has a minimal effect on quiescent cells in contrast to actively cycling cells that incur deamination and DNA damage. These data suggest that non-replicating cells may be relatively protected from mutagenesis by A3A, but that A3A poses a threat to genomic integrity of replicating progenitors.…”

Section: Discussionmentioning

confidence: 70%

“…[8][9][10][11] Although these deaminases have important physiologic functions in innate defense, their DNA mutator activity also threatens host genome integrity. [12][13][14] Deamination by AID outside of the Ig loci leads to off-target mutations and recurrent IgH-Myc translocations that drive B cell malignancies. 15,16 Similarly, somatic mutation clusters consistent with APOBEC3 activity have been recognized in tumor genomes, [17][18][19][20] suggesting deamination of the cellular genome by aberrant activity of APOBEC3 enzymes.…”

Section: Introductionmentioning

confidence: 99%

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APOBEC3A damages the cellular genome during DNA replication

et al. 2016

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The human APOBEC3 family of DNA-cytosine deaminases comprises 7 members (A3A-A3H) that act on single-stranded DNA (ssDNA). The APOBEC3 proteins function within the innate immune system by mutating DNA of viral genomes and retroelements to restrict infection and retrotransposition. Recent evidence suggests that APOBEC3 enzymes can also cause damage to the cellular genome. Mutational patterns consistent with APOBEC3 activity have been identified by bioinformatic analysis of tumor genome sequences. These mutational signatures include clusters of base substitutions that are proposed to occur due to APOBEC3 deamination. It has been suggested that transiently exposed ssDNA segments provide substrate for APOBEC3 deamination leading to mutation signatures within the genome. However, the mechanisms that produce single-stranded substrates for APOBEC3 deamination in mammalian cells have not been demonstrated. We investigated ssDNA at replication forks as a substrate for APOBEC3 deamination. We found that APOBEC3A (A3A) expression leads to DNA damage in replicating cells but this is reduced in quiescent cells. Upon A3A expression, cycling cells activate the DNA replication checkpoint and undergo cell cycle arrest. Additionally, we find that replication stress leaves cells vulnerable to A3A-induced DNA damage. We propose a model to explain A3A-induced damage to the cellular genome in which cytosine deamination at replication forks and other ssDNA substrates results in mutations and DNA breaks. This model highlights the risk of mutagenesis by A3A expression in replicating progenitor cells, and supports the emerging hypothesis that APOBEC3 enzymes contribute to genome instability in human tumors.

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

APOBEC3A damages the cellular genome during DNA replication

et al. 2016

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“…APOBEC3 proteins from the human APOBEC3 family of DNA cytosine deaminases are known as anti-HIV cellular proteins that impair viral DNA synthesis and integration by introducing G-to-A hypermutation to the viral genome (43, [392][393][394]. APOBEC3G physically interacts with HIV-1 integrase to prohibit the formation of proviral DNA (33).…”

Section: Vif-apobec3g-integrase Associationmentioning

confidence: 99%

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

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SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

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“…3,4 Recent studies have linked cancer progression and recurrence to A3 activity. [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.…”

Section: Introductionmentioning

confidence: 99%

“…[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%

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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APOBEC3 genes: retroviral restriction factors to cancer drivers

Cited by 106 publications

References 89 publications

APOBEC3A damages the cellular genome during DNA replication

APOBEC3A damages the cellular genome during DNA replication

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Determinants of Substrate Specificity in APOBEC3B

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