Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Venkatesan, S.; Angelova, Mihaela; Puttick, Clare; Zhai, Hao‐Ran; Caswell, Deborah R.; Lu, Wei-Ting; Dietzen, Michelle; Galanos, Panagiotis; Evangelou, Konstantinos; Bellelli, Roberto; Lim, Emilia L.; Watkins, Thomas B.K.; Rowan, Andrew; Teixeira, Vítor Hugo; Zhao, Yue; Chen, Haiquan; Ngo, Bryan; Zalmas, Lykourgos-Panagiotis; Bakir, Maise Al; Hobor, Sebastijan; Grönroos, Eva; Pennycuick, Adam; Nigro, Ersilia; Campbell, Brittany; Brown, William L.; Akarca, Ayse U.; Marafioti, Teresa; Wu, Mary; Howell, Michael; Boulton, Simon J.; Bertoli, Cosetta; Fenton, Tim R.; Bruin, Robertus A.M. de; Maya-Mendoza, Apolinar; Santoni-Rugiu, Eric; Hynds, Robert E.; Gorgoulis, Vassilis G.; Jamal‐Hanjani, Mariam; McGranahan, Nicholas; Harris, Reuben S.; Janes, Sam M.; Bártková, Jiřina; Bakhoum, Samuel F.; Bártek, Jiří; Kanu, Nnennaya; Swanton, Charles

doi:10.1158/2159-8290.cd-20-0725

Cited by 95 publications

(82 citation statements)

References 72 publications

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“…Importantly, the predominant pattern was APOBEC-driven, in agreement with the bioinformatic analysis of the GISAID database. Moreover, and in line with our presumption and our previous study [ 49 ], the SARS-CoV-2 induced senescent cells demonstrated significantly higher mRNA and protein levels of the APOBEC enzymes, particularly G and H (RNA editing cytoplasmic variants), which are reported to play a pivotal role in viral RNA editing [ 12 , 33 , 49 ]. Other mutation signatures were also found both in the cell culture isolated virome genomes and in the strains from GISAID, and maybe the outcome of the oxidative stress present in the senescent cells [ 51 ].…”

Section: Resultssupporting

confidence: 88%

“…This assumption was based on the fact that the apoptotic tolerant nature of senescent cells allows the virus to be hosted for longer periods compared to other cells with higher cell turnover [ 47 , 48 ], thus rendering the SARS-CoV-2 virome more susceptible to host mediated editing. APOBEC enzymes are well known to participate in viral genome editing [ 12 , 33 , 49 ]. Notably, we recently showed these enzymes to be highly expressed in senescent cells [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

“…APOBEC enzymes are well known to participate in viral genome editing [ 12 , 33 , 49 ]. Notably, we recently showed these enzymes to be highly expressed in senescent cells [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

“…Such a context can provide an extended time “window” for virus replication, therefore exposing its genome to host-mediated editing. Along this vein we showed that the senescent cell compartment acts as a “fertile” environment for mutational evolution of the virus, as it is more susceptible to APOBEC-3G and 3H RNA editing ( figure 6 ) [ 33 , 49 ]. Of course, other mechanisms extending survival and replication of SARS-CoV-2 may take place.…”

Section: Discussionmentioning

confidence: 99%

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Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis

et al. 2022

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BackgroundSARS-CoV-2 infection of the respiratory system can progress to a multi-systemic disease with aberrant inflammatory response. Cellular senescence promotes chronic inflammation, named as senescence-associated secretory phenotype (SASP). We investigated whether COVID-19 disease is associated with cellular senescence and SASP.MethodsAutopsy lung tissue samples from 11 COVID-19 patients and 43 age-matched non-COVID controls with similar comorbidities were analysed by immunohistochemistry for SARS-CoV-2, markers of senescence and key SASP cytokines. Virally-induced senescence was functionally recapitulated in vitro, by infecting epithelial Vero-E6 cells and a three-dimensional alveosphere system of alveolar type 2 (AT2) cells with SARS-CoV-2 strains isolated from COVID-19 patients.ResultsSARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in AT2 cells. Infected AT2 cells expressed the angiotensin-converting-enzyme 2 (ACE2) and exhibited increased senescence (p16INK4A and SenTraGorTM positivity) and IL-1β and IL-6 expression. In vitro, infection of Vero-E6 cells with SARS-CoV-2 induced senescence (SenTraGorTM), DNA damage (γ-H2AX) and increased cytokine (IL-1β, IL-6, CXCL8) and Apolipoprotein B mRNA-editing (APOBEC) enzyme expression. Next-generation-sequencing analysis of progenies obtained from infected/senescent Vero-E6 cells demonstrated APOBEC-mediated SARS-CoV-2 mutations. Dissemination of the SARS-CoV-2-infection and senescence was confirmed in extra-pulmonary sites (kidney and liver) of a COVID-19 patient.ConclusionsWe demonstrate that in severe COVID-19, AT2 cells infected by SARS-CoV-2 exhibit senescence and a proinflammatory phenotype. In vitro, SARS-CoV-2 infection induces senescence and inflammation. Importantly, infected senescent cells may act as a source of SARS-CoV-2 mutagenesis mediated by APOBEC enzymes. Therefore, SARS-CoV-2-induced senescence may be an important molecular mechanism of severe COVID-19, disease persistence and mutagenesis.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

“…APOBEC enzymes are well known to participate in viral genome editing [ 12 , 33 , 49 ]. Notably, we recently showed these enzymes to be highly expressed in senescent cells [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis

et al. 2022

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“…Similarly, BFB cycles have been shown to generate increasing amounts of chromothripsis by providing free DNA ends that can engage in genomic rearrangement and by compromising centromere function (Umbreit et al , 2020). DNA replication stress has been shown to drive genomic instability by promoting both structural and numerical chromosomal aberrations (Burrell et al , 2013) and by triggering single nucleotide‐level mutagenesis mediated via APOBEC3B induction (Kanu et al , 2016), which in turn leads to incomplete replication of genomic DNA (Venkatesan et al , 2021). Relatedly, regional mutational clusters (kataegis) (Stephens et al , 2011) and lesion segregation (Aitken et al , 2020) have also been shown in some instances to be associated with chromothripsis and other rearrangement architectures (Nik‐Zainal et al , 2012a).…”

Section: Introductionmentioning

confidence: 99%

Cancer evolution: Darwin and beyond

2021

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Clinical and laboratory studies over recent decades have established branched evolution as a feature of cancer. However, while grounded in somatic selection, several lines of evidence suggest a Darwinian model alone is insufficient to fully explain cancer evolution. First, the role of macroevolutionary events in tumour initiation and progression contradicts Darwin's central thesis of gradualism. Whole-genome doubling, chromosomal chromoplexy and chromothripsis represent examples of single catastrophic events which can drive tumour evolution. Second, neutral evolution can play a role in some tumours, indicating that selection is not always driving evolution. Third, increasing appreciation of the role of the ageing soma has led to recent generalised theories of age-dependent carcinogenesis. Here, we review these concepts and others, which collectively argue for a model of cancer evolution which extends beyond Darwin. We also highlight clinical opportunities which can be grasped through targeting cancer vulnerabilities arising from non-Darwinian patterns of evolution.

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circCIMT Silencing Promotes Cadmium‐Induced Malignant Transformation of Lung Epithelial Cells Through the DNA Base Excision Repair Pathway

Chen

Cui

et al. 2023

Advanced Science

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Changes in gene expression in lung epithelial cells are detected in cancer tissues during exposure to pollutants, highlighting the importance of gene‐environmental interactions in disease. Here, a Cd‐induced malignant transformation model in mouse lungs and bronchial epithelial cell lines is constructed, and differences in the expression of non‐coding circRNAs are analyzed. The migratory and invasive abilities of Cd‐transformed cells are suppressed by circCIMT. A significant DNA damage response is observed after exposure to Cd, which increased further following circCIMT‐interference. It is found that APEX1 is significantly down‐regulated following Cd exposure. Furthermore, it is demonstrated that circCIMT bound to APEX1 during Cd exposure to mediate the DNA base excision repair (BER) pathway, thereby reducing DNA damage. In addition, simultaneous knockdown of both circCIMT and APEX1 promotes the expression of cancer‐related genes and malignant transformation after long‐term Cd exposure. Overall, these findings emphasis the importance of genetic‐epigenetic interactions in chemical‐induced cancer transformation.

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Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Abstract: The version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record.

Cited by 95 publications

References 72 publications

Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis

Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis

Cancer evolution: Darwin and beyond

circCIMT Silencing Promotes Cadmium‐Induced Malignant Transformation of Lung Epithelial Cells Through the DNA Base Excision Repair Pathway

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