APOBEC3 proteins and genomic stability

Narvaiza, Iñigo; Weitzman, Matthew D.

doi:10.4161/cc.11.1.18706

Cited by 16 publications

(12 citation statements)

References 109 publications

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“…The induction of mutation clusters in yeast through expression of these enzymes is dependent on activity of the uracil DNA glycosylase Ung1, indicating that in addition to transcription intermediates, DNA repair intermediates can also serve as substrates (Taylor et al, 2013). In human cells, an A3A-induced increase in γ-H2AX foci requires cells to be in S-phase (Landry et al, 2011, Narvaiza et al, 2012), suggesting that this enzyme may deaminate ssDNA formed during DNA replication and ultimately induce DNA double strand breaks (DSBs) via subsequent enzymatic processing of the deoxyuridine by base excision repair. Nevertheless, the chromosomal substrates for A3A- and A3B-induced mutagenesis, remain undefined.…”

Section: Introductionmentioning

confidence: 99%

APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication

et al. 2016

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Summary APOBEC family cytidine deaminases have been recently implicated as powerful mutators of cancer genomes. How APOBECs, which are ssDNA specific enzymes, gain access to chromosomal DNA is unclear. To ascertain the chromosomal ssDNA substrates of the APOBECs, we expressed APOBEC3A and APOBEC3B, the two most probable APOBECs mediating cancer mutagenesis, in a yeast model system. We demonstrate, using mutation reporters and whole genome sequencing, that APOBEC3A- and APOBEC3B-induced mutagenesis primarily results from the deamination of the lagging strand template during DNA replication. Moreover, our results indicate that both genetic deficiencies in replication fork-stabilizing proteins and chemical induction of replication stress greatly augment the mutagenesis of APOBEC3A and 3B. Taken together, these results strongly indicate that ssDNA formed during DNA lagging strand synthesis is a major substrate for APOBECs and may be the principal substrate in human cancers experiencing replication stress.

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Section: Introductionmentioning

confidence: 99%

APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication

et al. 2016

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“…In addition A3A is involved in clearance of foreign dsDNA from cells (12). Hence, cellular APOBEC3 deaminases act as potent innate antiviral restriction factors, but may also have diverse effects on genomic regulation and stability (13). …”

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confidence: 99%

APOBEC3 Cytidine Deaminases in Double-Strand DNA Break Repair and Cancer Promotion

Nowarski

Kotler

2013

Cancer Research

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High frequency of cytidine to thymidine conversions were identified in the genome of several types of cancer cells. In breast cancer cells these mutations are clustered in long DNA regions associated with ssDNA, double-strand DNA breaks (DSBs) and genomic rearrangements. The observed mutational pattern resembles the deamination signature of cytidine to uridine carried out by members of the APOBEC3 family of cellular deaminases. Consistently, APOBEC3B (A3B) was recently identified as the mutational source in breast cancer cells. A3G is another member of the cytidine deaminases family predominantly expressed in lymphoma cells, where it is involved in mutational DSB repair following ionizing radiation treatments. This activity provides us with a new paradigm for cancer cell survival and tumor promotion and a mechanistic link between ssDNA, DSBs and clustered mutations.

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“…[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%

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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APOBEC3 proteins and genomic stability

Cited by 16 publications

References 109 publications

APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication

APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication

APOBEC3 Cytidine Deaminases in Double-Strand DNA Break Repair and Cancer Promotion

APOBEC3A damages the cellular genome during DNA replication

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