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

Nowarski, Roni; Kotler, Moshe

doi:10.1158/0008-5472.can-13-0728

Cited by 52 publications

(53 citation statements)

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“…In addition, frequent mutations that can be ascribed to hA3B and hA3A (5=-TC context) were found in host DNA sequences of other cancers, including bladder, cervix, lung, and head-and-neck cancers (25). Kataegis were frequently found near chromosome rearrangement breakpoints (27), and hA3A can induce DNA breaks and activate DNA damage responses (30,74,75). Thus, hA3A may also contribute to cancer development due to its potential genotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…This hypothesis states that hA3 proteins introduce critical mutations in host genomes that eventually promote cancer progression (19,26,28). Other studies suggested that genomic mutations following double-strand DNA breaks could also be induced by hA3 (29,30). Notably, hA3-associated mutational signatures are highly enriched in HPV-positive cervical and headand-neck cancers (26,31,32).…”

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confidence: 99%

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APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

Warren

Guo

et al. 2015

J Virol

176

203

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Human papillomaviruses (HPVs) are small DNA viruses causally associated with benign warts and multiple cancers, including cervical and head-and-neck cancers. While the vast majority of people are exposed to HPV, most instances of infection are cleared naturally. However, the intrinsic host defense mechanisms that block the early establishment of HPV infections remain mysterious. Several antiviral cytidine deaminases of the human APOBEC3 (hA3) family have been identified as potent viral DNA mutators. While editing of HPV genomes in benign and premalignant cervical lesions has been demonstrated, it remains unclear whether hA3 proteins can directly inhibit HPV infection. Interestingly, recent studies revealed that HPV-positive cervical and head-and-neck cancers exhibited higher rates of hA3 mutation signatures than most HPV-negative cancers. Here, we report that hA3A and hA3B expression levels are highly upregulated in HPV-positive keratinocytes and cervical tissues in early stages of cancer progression, potentially through a mechanism involving the HPV E7 oncoprotein. HPV16 virions assembled in the presence of hA3A, but not in the presence of hA3B or hA3C, have significantly decreased infectivity compared to HPV virions assembled without hA3A or with a catalytically inactive mutant, hA3A/E72Q. Importantly, hA3A knockdown in human keratinocytes results in a significant increase in HPV infectivity. Collectively, our findings suggest that hA3A acts as a restriction factor against HPV infection, but the induction of this restriction mechanism by HPV may come at a cost to the host by promoting cancer mutagenesis. IMPORTANCEHuman papillomaviruses (HPVs) are highly prevalent and potent human pathogens that cause >5% of all human cancers, including cervical and head-and-neck cancers. While the majority of people become infected with HPV, only 10 to 20% of infections are established as persistent infections. This suggests the existence of intrinsic host defense mechanisms that inhibit viral persistence. Using a robust method to produce infectious HPV virions, we demonstrate that hA3A, but not hA3B or hA3C, can significantly inhibit HPV infectivity. Moreover, hA3A and hA3B were coordinately induced in HPV-positive clinical specimens during cancer progression, likely through an HPV E7 oncoprotein-dependent mechanism. Interestingly, HPV-positive cervical and head-and-neck cancer specimens were recently shown to harbor significant amounts of hA3 mutation signatures. Our findings raise the intriguing possibility that the induction of this host restriction mechanism by HPV may also trigger hA3A-and hA3B-induced cancer mutagenesis. Human papillomaviruses (HPVs) are small, nonenveloped DNA viruses known as one of the most prevalent sexually transmitted pathogens. Among almost 200 different genotypes, ϳ24 high-risk HPV genotypes are causally associated with multiple human cancers, including nearly all cervical cancers and a portion of head-and-neck squamous cell carcinomas (1). From 1988 to 2004, the incidence of HPV-associ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

Warren

Guo

et al. 2015

J Virol

176

203

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“…Interestingly, recent work from Halemano and co-workers showed evidence that mouse APOBEC3 mutates immunoglobulin heavy chain variable genes (IgV) during retroviral infections, demonstrating thereby a previously unidentified function of APOBEC3 in generating virus-specific neutralizing antibodies and highlighting a new mechanism for antibody diversification in vivo [50]. In addition, APOBEC3 has also been attributed a role in double-strand break (DSB) DNA repair by non-homologous end joining (NHEJ) [51,52]. Expression of APOBEC3G in lymphoma cells associates with efficient DSB repair, whereas inhibition of APOBEC3G expression or deamination activity results in impaired joining of DSBs by NHEJ, implying a prosurvival role of APOBEC3 in lymphoma cells [51].…”

Section: Introductionmentioning

confidence: 99%

AID/APOBEC deaminases and cancer

et al. 2015

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Mutations are the basis for evolution and the development of genetic diseases. Especially in cancer, somatic mutations in oncogenes and tumor suppressor genes alongside the occurrence of passenger mutations have been observed by recent deep-sequencing approaches. While mutations have long been considered random events induced by DNA-replication errors or by DNA damaging agents, genome sequencing led to the discovery of non-random mutation signatures in many human cancer. Common non-random mutations comprise DNA strand-biased mutation showers and mutations restricted to certain DNA motifs, which recently have become attributed to the activity of the AID/APOBEC family of DNA deaminases. Hence, APOBEC enzymes, which have evolved as key players in natural and adaptive immunity, have been proposed to contribute to cancer development and clonal evolution of cancer by inducing collateral genomic damage due to their DNA deaminating activity. This review focuses on how mutagenic events through AID/APOBEC deaminases may contribute to cancer development.

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“…[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 …”

Section: Introductionmentioning

confidence: 99%

“…[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. 18 Each A3 protein consists of either one or two deaminase domains.…”

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

Cited by 52 publications

References 50 publications

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

AID/APOBEC deaminases and cancer

Determinants of Substrate Specificity in APOBEC3B

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