ADAR2-mediated RNA editing of DNA:RNA hybrids is required for DNA double strand break repair

Jimeno, Sonia; Prados-Carvajal, Rosario; Fernández-Ávila, María Jesús; Silva, Sónia; Silvestris, Domenico Alessandro; Endara-Coll, Martin; Domingo-Prim, Judit; Mejías-Navarro, Fernando; Rodríguez-Real, Guillermo; Romero-Franco, Amador; Jimeno-González, Silvia; Barroso, Sónia; Cesarini, Valeriana; Aguilera, Andrés; Gallo, Angela; Visa, Neus; Huertas, Pablo

doi:10.1101/2021.03.24.436729

Cited by 4 publications

(4 citation statements)

References 71 publications

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“…7C). This is consistent with the recent observations that ADAR2 activity can dissolve DNA:RNA hybrids (14) decreasing the amount of cytosolic DNA able to activate STING. The release of cytosolic DNA was supported by the activation of senescence-associated β-galactosidase activity (59,60) in Mero95 ADAR2 KD cells (Fig.…”

Section: Adar2 and Tumor Microenvironmentsupporting

confidence: 93%

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Heterogeneity of RNA editing in mesothelioma and how RNA editing enzyme ADAR2 affects mesothelioma cell growth, response to chemotherapy and tumor microenvironment

Hariharan

Rehrauer

et al. 2022

Preprint

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We previously observed increased levels of adenosine-deaminase-acting-on-dsRNA (Adar)-dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR-dependent RNA editing in mesothelioma. Tumors and mesothelioma primary cultures have higher ADAR-mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1-associated protein 1 wild-type tumors, with corresponding changes in RNA editing in transcripts and 3-UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment and type-1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures.

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Section: Adar2 and Tumor Microenvironmentsupporting

confidence: 93%

“…ADAR1 p110 was found to edit RNA in DNA:RNA hybrids leading to the resolution of Rloops, promoting proliferation of cancer cells (13). Similarly, dissolution of DNA:RNA hybrids by ADAR2mediated editing rendered cancer cells resistant to genotoxic agents and decreases genomic instability (14).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of RNA editing in mesothelioma and how RNA editing enzyme ADAR2 affects mesothelioma cell growth, response to chemotherapy and tumor microenvironment

Hariharan

Rehrauer

et al. 2022

Preprint

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“…45 Moreover, ADAR2 not only plays an important role in the recoding of specific transcripts but also influences DNA repair that is dependent on ADAR2-editing of DNA:RNA hybrids to ease their dissolution. 46 ADARB1 was more highly expressed after PMA treatment but was repressed in shKHS-RP-treated THP-1 cells. In addition, we identified differences in the alternative intron of ADARB1 after PMA and shKHSRP treatment, in that the 5' splice site differed while the 3' splice site was the same.…”

Section: Khsrp Combines Transcriptional and Posttranscriptional Regul...mentioning

confidence: 88%

KHSRP combines transcriptional and posttranscriptional mechanisms to regulate monocytic differentiation

Wang

et al. 2022

Blood Science

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RNA-binding proteins (RBPs) are widely involved in the transcriptional and posttranscriptional regulation of multiple biological processes. The transcriptional regulatory ability of RBPs was indicated by the identification of chromatin-enriched RBPs (Che-RBPs). One of these proteins, KH-type splicing regulatory protein (KHSRP), is a multifunctional RBP that has been implicated in mRNA decay, alternative splicing, and miRNA biogenesis and plays an essential role in myeloid differentiation by facilitating the maturation of miR-129. In this study, we revealed that KHSRP regulates monocytic differentiation by regulating gene transcription and RNA splicing. KHSRP-occupied specific genomic sites in promoter and enhancer regions to regulate the expression of several hematopoietic genes through transcriptional activation and bound to pre-mRNA intronic regions to modulate alternative splicing during monocytic differentiation. Of note, KHSRP had co-regulatory effects at both the transcriptional and posttranscriptional levels on MOGOH and ADARB1. Taken together, our analyses revealed the dual DNA- and RNA-binding activities of KHSRP and have provided a paradigm to guide the analysis of other functional Che-RBPs in different biological systems.

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“…In contrast, we have argued that the evolutionary increase through the generations in the rate of RNA editing directly and mechanistically generates an increase in the rate of the corresponding DNA mutation in the corresponding positions (Melamed et al, 2022). Indeed, evidence has been accumulated suggesting a mechanistic connection between RNA editing and DNA mutation either by ADAR acting directly to mutate transcribed DNA (Shiromoto et al, 2021;Jimeno et al, 2021;Zheng et al, 2017;Tsuruoka et al, 2013) or via reverse transcriptase activity of several DNA polymerases (Chandramouly et al, 2021;Su et al, 2019;Franklin et al, 2004) using edited RNA as a template. 1…”

Section: Mutational Replacement Of Rna Editingmentioning

confidence: 99%

Evolutionary Honing in and Mutational Replacement: How Long-Term Directed Mutational Responses to Specific Environmental Pressures Are Possible

Livnat¹,

Melamed²

2022

Preprint

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Recent results have shown that the human malaria-resistant hemoglobin S mutation originates de novo more frequently in the gene and in the population where it is of adaptive significance, namely, in the hemoglobin subunit beta gene compared to the non-resistant but otherwise identical 20A>T mutation in the hemoglobin subunit delta gene, and in sub-Saharan Africans, who have been subject to intense malarial pressure for many generations, compared to Northern Europeans, who have not. This finding raises a fundamental challenge to the traditional notion of accidental mutation. Here we address this finding with the replacement hypothesis, according to which pre-existing genetic interactions can lead directly and mechanistically to mutations that simplify and replace them. Thus, a gradual evolutionary process under selection can hone in on interactions of importance for the currently evolving adaptations, from which large-effect mutations follow that are relevant to these adaptations. We exemplify this hypothesis using multiple types of mutation, including gene fusion mutations, gene duplication mutations, A>G mutations in RNA-edited sites and transcription-associated mutations, and place it in the broader context of a system-level view of mutation origination called Interaction-based Evolution. Potential consequences include that similarity of mutation pressures may contribute to parallel evolution in genetically related species, that the evolution of genome organization may be driven by mutational mechanisms, that transposable element movements may also be explained by replacement, and that long-term directional mutational responses to specific environmental pressures are possible. Such responses need to be further tested by future studies in natural and artificial settings.

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ADAR2-mediated RNA editing of DNA:RNA hybrids is required for DNA double strand break repair

Cited by 4 publications

References 71 publications

Heterogeneity of RNA editing in mesothelioma and how RNA editing enzyme ADAR2 affects mesothelioma cell growth, response to chemotherapy and tumor microenvironment

Heterogeneity of RNA editing in mesothelioma and how RNA editing enzyme ADAR2 affects mesothelioma cell growth, response to chemotherapy and tumor microenvironment

KHSRP combines transcriptional and posttranscriptional mechanisms to regulate monocytic differentiation

Evolutionary Honing in and Mutational Replacement: How Long-Term Directed Mutational Responses to Specific Environmental Pressures Are Possible

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