ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells

Shiromoto, Yusuke; Sakurai, Masayuki; Minakuchi, Moeko; Ariyoshi, Kentaro; Nishikura, Kazuko

doi:10.1038/s41467-021-21921-x

Cited by 70 publications

(52 citation statements)

References 74 publications

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“…The deregulation of genes involved in immunity is likely elicited by the silencing of the p150 ADAR1 isoform. However, other biological processes related to the p110 isoform [56], also silenced in our study, were deregulated, such as DNA damage checkpoint (GO:0,000,077). It is highly probable that both ADAR1 isoforms contribute to the growth defect observed in vitro and in vivo after ADAR1 silencing [57]; however, our study design did not allow us to distinguish the specific isoform responsible for CDK13 editing and this should be addressed in a future study.…”

Section: Discussionmentioning

confidence: 54%

An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks

et al. 2021

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Background Adenosine deaminases acting on RNA (ADARs) modify many cellular RNAs by catalyzing the conversion of adenosine to inosine (A-to-I), and their deregulation is associated with several cancers. We recently showed that A-to-I editing is elevated in thyroid tumors and that ADAR1 is functionally important for thyroid cancer cell progression. The downstream effectors regulated or edited by ADAR1 and the significance of ADAR1 deregulation in thyroid cancer remain, however, poorly defined. Methods We performed whole transcriptome sequencing to determine the consequences of ADAR1 deregulation for global gene expression, RNA splicing and editing. The effects of gene silencing or RNA editing were investigated by analyzing cell viability, proliferation, invasion and subnuclear localization, and by protein and gene expression analysis. Results We report an oncogenic function for CDK13 in thyroid cancer and identify a new ADAR1-dependent RNA editing event that occurs in the coding region of its transcript. CDK13 was significantly over-edited (c.308A > G) in tumor samples and functional analysis revealed that this editing event promoted cancer cell hallmarks. Finally, we show that CDK13 editing increases the nucleolar abundance of the protein, and that this event might explain, at least partly, the global change in splicing produced by ADAR1 deregulation. Conclusions Overall, our data support A-to-I editing as an important pathway in cancer progression and highlight novel mechanisms that might be used therapeutically in thyroid and other cancers.

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Section: Discussionmentioning

confidence: 54%

An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks

et al. 2021

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“…Although the majority of research efforts to understand mechanisms of R-loop regulation has focused on the helicase family of proteins for their ability to resolve these structures 12 , 13 , 22 , 30 , 33 , 69 , several reports also implicate proteins without known helicase activity in R-loop regulation 20 , 21 , 70 . Replication protein A (RPA), a single-strand DNA binding protein, is known to localize to R-loop structures in vivo where it stimulates the activity of RNase H to disrupt R-loops 20 .…”

Section: Discussionmentioning

confidence: 99%

Proximity labeling identifies a repertoire of site-specific R-loop modulators

et al. 2022

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R-loops are three-stranded nucleic acid structures that accumulate on chromatin in neurological diseases and cancers and contribute to genome instability. Using a proximity-dependent labeling system, we identified distinct classes of proteins that regulate R-loops in vivo through different mechanisms. We show that ATRX suppresses R-loops by interacting with RNAs and preventing R-loop formation. Our proteomics screen also discovered an unexpected enrichment for proteins containing zinc fingers and homeodomains. One of the most consistently enriched proteins was activity-dependent neuroprotective protein (ADNP), which is frequently mutated in ASD and causal in ADNP syndrome. We find that ADNP resolves R-loops in vitro and that it is necessary to suppress R-loops in vivo at its genomic targets. Furthermore, deletion of the ADNP homeodomain severely diminishes R-loop resolution activity in vitro, results in R-loop accumulation at ADNP targets, and compromises neuronal differentiation. Notably, patient-derived human induced pluripotent stem cells that contain an ADNP syndrome-causing mutation exhibit R-loop and CTCF accumulation at ADNP targets. Our findings point to a specific role for ADNP-mediated R-loop resolution in physiological and pathological neuronal function and, more broadly, to a role for zinc finger and homeodomain proteins in R-loop regulation, with important implications for developmental disorders and cancers.

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“…5B ). Interestingly, it was previously shown that R-loops at telomeres can be edited by ADAR1 37 , leading to A→I edits 38 and a large body of evidence now supports the idea that these RNA editing enzymes tend to exhibit off-target effects. Because inosine pairs with cytosine, such off-target editing events on genomic R-loops could be reported as A→G errors by our circ-seq assay.…”

Section: Resultsmentioning

confidence: 91%

The fidelity of transcription in human cells

Chung

Verheijen

Zhang³

et al. 2022

Preprint

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Accurate transcription is required for the faithful expression of genetic information. To provide insight into the molecular mechanisms that control the fidelity of transcription, we analyzed the landscape of transcription errors in human embryonic stem cells. These measurements provide the first reasonable estimate of the fidelity of transcription in human cells and identify multiple genetic and epigenetic factors that control its accuracy. In addition, we developed a new reporter mouse to identify cell types and tissues that commit these errors the most. These experiments revealed that CA1 and dentate gyrus neurons are highly sensitive to transcriptional mutagenesis, lending new support to the hypothesis that transcription errors play a role in the progression of Alzheimer’s disease. Taken together, these experiments provide unprecedented insight into the fidelity of gene expression in human cells and the molecular mechanisms that govern the central dogma of life.

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ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells

Cited by 70 publications

References 74 publications

An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks

An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks

Proximity labeling identifies a repertoire of site-specific R-loop modulators

The fidelity of transcription in human cells

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