APOBEC3G enhances lymphoma cell radioresistance by promoting cytidine deaminase-dependent DNA repair

Nowarski, Roni; Wilner, Ofer I.; Cheshin, Ori; Shahar, Or David; Kenig, Edan; Baraz, Leah; Britan-Rosich, Elena; Nagler, Arnon; Harris, Reuben S.; Goldberg, Michal; Willner, Itamar; Kotler, Moshe

doi:10.1182/blood-2012-01-402123

Cited by 63 publications

(82 citation statements)

References 47 publications

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“…To interpret the functional impact of the changes observed it is important to keep in mind that: IFIT1 and IFIT3 are both implicated to function against viral infections (19); OASL functions in antiviral response (20); AZU1 serves as an important mediator during the initiation of the immune response (30); and APOBEC3G promotes cytidine deaminase-dependent DNA repair to render radiation resistance in lymphoma (48). In addition, IFN-inducible IFITM proteins (IFITM1, 2 and 3) inhibit the replication of various viruses including HIV-1 (21).…”

Section: Discussionmentioning

confidence: 99%

Defining Molecular Signature of Pro-Immunogenic Radiotherapy Targets in Human Prostate Cancer Cells

et al. 2014

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To understand the impact of clinically relevant radiation therapy (RT) on tumor immune gene expression and to utilize the changes that occur during treatment to improve cancer treatment outcome, we examined how immune response genes are modulated in prostate cancer cells of varying p53 status. LNCaP (p53 wild-type), PC3 (p53 null) and DU145 (p53 mutant) cells received a 10 Gy single dose or 1 Gy × 10 multifractionated radiation dose to simulate hypofractionated and conventionally fractionated prostate radiotherapy. Total RNA was isolated 24 h after multi-fractionated radiation treatment and single-dose treatments and subjected to microarray analysis and later validated by RT-PCR. RT-PCR was utilized to identify total-dose inflection points for significantly upregulated genes in response to multifractionated radiation therapy. Radiation-induced damage-associated molecular pattern molecules (DAMPs) and cytokine analyses were performed using bioluminescence and ELISA. Multifractionated doses activated immune response genes more robustly than single-dose treatment, with a relatively larger number of immune genes upregulated in PC3 compared to DU145 and LNCaP cells. The inflection point of multifractionated radiation-induced immune genes in PC3 cells was observed in the range of 8–10 Gy total radiation dose. Although both multifractionated and single-dose radiation-induced proinflammatory DAMPs and positively modulated the cytokine environment, the changes were of higher magnitude with multifractionated therapy. The findings of this study together with the gene expression data suggest that cells subjected to multifractionated radiation treatment would promote productive immune cell–tumor cell interactions.

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Section: Discussionmentioning

confidence: 99%

Defining Molecular Signature of Pro-Immunogenic Radiotherapy Targets in Human Prostate Cancer Cells

et al. 2014

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“…The prevailing notion of A3G being maintained under strict control, limiting its localization to the cytoplasm, has been brought into question by several studies that demonstrated it can be partially localized to the nuclear compartment (Stopak et al 2003;Hill et al 2006;Depboylu et al 2007). It has also been shown that A3G can be recruited to doublestrand breaks in genomic DNA (Nowarski et al 2012) and that it may shuttle to the nucleus in response against LINE-1 retrotransposition (Kinomoto et al 2007). A3G expression in the germline and its small nuclear fraction, both fundamental conditions for inherited mutagenesis, provide a window of opportunity for the contribution of A3G to genome evolution.…”

Section: Enzyme-induced Genome Evolution By Apobec3gmentioning

confidence: 99%

Clustered mutations in hominid genome evolution are consistent with APOBEC3G enzymatic activity

et al. 2016

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The gradual accumulation of mutations by any of a number of mutational processes is a major driving force of divergence and evolution. Here, we investigate a potentially novel mutational process that is based on the activity of members of the AID/ APOBEC family of deaminases. This gene family has been recently shown to introduce-in multiple types of cancer-enzyme-induced clusters of co-occurring somatic mutations caused by cytosine deamination. Going beyond somatic mutations, we hypothesized that APOBEC3-following its rapid expansion in primates-can introduce unique germline mutation clusters that can play a role in primate evolution. In this study, we tested this hypothesis by performing a comprehensive comparative genomic screen for APOBEC3-induced mutagenesis patterns across different hominids. We detected thousands of mutation clusters introduced along primate evolution which exhibit features that strongly fit the known patterns of APOBEC3G mutagenesis. These results suggest that APOBEC3G-induced mutations have contributed to the evolution of all genomes we studied. This is the first indication of site-directed, enzyme-induced genome evolution, which played a role in the evolution of both modern and archaic humans. This novel mutational mechanism exhibits several unique features, such as its higher tendency to mutate transcribed regions and regulatory elements and its ability to generate clusters of concurrent point mutations that all occur in a single generation. Our discovery demonstrates the exaptation of an anti-viral mechanism as a new source of genomic variation in hominids with a strong potential for functional consequences.

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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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APOBEC3G enhances lymphoma cell radioresistance by promoting cytidine deaminase-dependent DNA repair

Cited by 63 publications

References 47 publications

Defining Molecular Signature of Pro-Immunogenic Radiotherapy Targets in Human Prostate Cancer Cells

Defining Molecular Signature of Pro-Immunogenic Radiotherapy Targets in Human Prostate Cancer Cells

Clustered mutations in hominid genome evolution are consistent with APOBEC3G enzymatic activity

AID/APOBEC deaminases and cancer

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