Genotoxic stress and viral infection induce transient expression of APOBEC3A and pro-inflammatory genes through two distinct pathways

Oh, Sunwoo; Bournique, Elodie; Bowen, Danae; Jalili, Pégah; Sanchez, Ambrocio; Ward, I. M.; Dananberg, Alexandra; Manjunath, Lavanya; Tran, Genevieve P.; Semler, Bert L.; Maciejowski, John; Seldin, Marcus M.; Buisson, Rémi

doi:10.1038/s41467-021-25203-4

Cited by 38 publications

(27 citation statements)

References 86 publications

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“…We next sought to identify the innate immune signaling pathway(s) responsible for A3B re-localization after SeV infection. Consistent with previous studies 65,[68][69][70] , SeV infection triggered STAT1 phosphorylation mediated by the RIG-I/MAVS-induced IFN signaling pathway along with both PKR and EIF2α phosphorylation, as evidence of activation of the PKR signaling pathway (Fig. 1h).…”

Section: Apobec3b Is Recruited To Stress Granules After Sev Infectionsupporting

confidence: 92%

APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection

Manjunath

Ortega

et al. 2023

Nat Commun

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Double-stranded RNA produced during viral replication and transcription activates both protein kinase R (PKR) and ribonuclease L (RNase L), which limits viral gene expression and replication through host shutoff of translation. In this study, we find that APOBEC3B forms a complex with PABPC1 to stimulate PKR and counterbalances the PKR-suppressing activity of ADAR1 in response to infection by many types of viruses. This leads to translational blockage and the formation of stress granules. Furthermore, we show that APOBEC3B localizes to stress granules through the interaction with PABPC1. APOBEC3B facilitates the formation of protein-RNA condensates with stress granule assembly factor (G3BP1) by protecting mRNA associated with stress granules from RNAse L-induced RNA cleavage during viral infection. These results not only reveal that APOBEC3B is a key regulator of different steps of the innate immune response throughout viral infection but also highlight an alternative mechanism by which APOBEC3B can impact virus replication without editing viral genomes.

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Section: Apobec3b Is Recruited To Stress Granules After Sev Infectionsupporting

confidence: 92%

APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection

Manjunath

Ortega

et al. 2023

Nat Commun

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“…It is therefore remarkable here that the overall genome-wide level of APOBEC3 signature mutation from A3A is only ~4-fold higher than that attributable to A3B. Endogenous A3A and A3B also have both distinct and overlapping transcription programs, and both genes can be induced by a variety of conditions including viral infection and inflammation (Argyris et al, 2020; Cho et al, 2018; Leonard et al, 2015; Maruyama et al, 2016; Oh et al, 2021; Periyasamy et al, 2015; Periyasamy et al, 2017; Roelofs et al, 2020; Starrett et al, 2019; Verhalen et al, 2016; Vieira et al, 2014; Warren, Westrich, Doorslaer, & Pyeon, 2017; Warren et al, 2015; Westrich et al, 2018). In vivo , A3A and A3B gene expression is also likely to be affected by the local tumor microenvironment, which can vary both between and within cancer types, as well as by a patient’s global state of health.…”

Section: Discussionmentioning

confidence: 86%

Mutational impact of APOBEC3A and APOBEC3B in a human cell line and comparisons to breast cancer

Jarvis

Carpenter

Temiz

et al. 2022

Preprint

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A prominent source of mutation in cancer is single-stranded DNA cytosine deamination by cellular APOBEC3 enzymes, which results in C-to-T and C-to-G mutations in TCA and TCT motifs. Although multiple enzymes have been implicated, reports conflict and it is unclear which enzyme(s) are responsible. Here we develop a selectable system to quantify genome mutation and compare the mutagenic activities of three leading candidates - APOBEC3A, APOBEC3B, and APOBEC3H. The human cell line, HAP1, was engineered to express the thymidine kinase (TK) gene of HSV-1, which confers sensitivity to ganciclovir. Clonal expression of APOBEC3A and APOBEC3B, but not catalytic mutant controls or APOBEC3H, triggered elevated DNA damage responses and increased frequencies of TK mutation. Mutant TK DNA sequences revealed nearly indistinguishable cytosine mutation patterns. Whole genome sequences from TK mutant clones confirmed these results and enabled broader bioinformatic analyses. Most importantly, comparisons of “pure” APOBEC3A- and APOBEC3B-inflicted mutation signatures from this system and the actual APOBEC3 signature from breast cancer indicated that most tumors manifest a composite signature. These studies help resolve a long-standing etiologic debate in the cancer field and indicate that future diagnostic and therapeutic efforts should focus on both APOBEC3A and APOBEC3B.

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“…APOBEC seems also to be responsible of the Kataegis and appears to be linked with nuclear envelope disruption rupture [ 60 , 61 ]. Interestingly, DNA damage and replication stress also seems to stimulate the expression of this enzyme [ 104 ]. The second, is the cGAS/STING pathway, a recently discovered pathway [ 105 ].…”

Section: Discussionmentioning

confidence: 99%

Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

Gauthier

Lorenzo

Comaills

2021

Cancers

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During metastasis, invading tumor cells and circulating tumor cells (CTC) face multiple mechanical challenges during migration through narrow pores and cell squeezing. However, little is known on the importance and consequences of mechanical stress for tumor progression and success in invading a new organ. Recently, several studies have shown that cell constriction can lead to nuclear envelope rupture (NER) during interphase. This loss of proper nuclear compartmentalization has a profound effect on the genome, being a key driver for the genome evolution needed for tumor progression. More than just being a source of genomic alterations, the transient nuclear envelope collapse can also support metastatic growth by several mechanisms involving the innate immune response cGAS/STING pathway. In this review we will describe the importance of the underestimated role of cellular squeezing in the progression of tumorigenesis. We will describe the complexity and difficulty for tumor cells to reach the metastatic site, detail the genomic aberration diversity due to NER, and highlight the importance of the activation of the innate immune pathway on cell survival. Cellular adaptation and nuclear deformation can be the key to the metastasis success in many unsuspected aspects.

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Genotoxic stress and viral infection induce transient expression of APOBEC3A and pro-inflammatory genes through two distinct pathways

Cited by 38 publications

References 86 publications

APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection

APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection

Mutational impact of APOBEC3A and APOBEC3B in a human cell line and comparisons to breast cancer

Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

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