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The long non-coding RNA LINDA restrains cellular collapse following DNA damage in Arabidopsis thaliana

ABSTRACT: The genomic integrity of every organism is endangered by various intrinsic and extrinsic stresses. To maintain the genomic integrity, a sophisticated DNA damage response (DDR) network is activated rapidly after DNA damage. Notably, the fundamental DDR mechanisms are conserved in eukaryotes. However, knowledge about many regulatory aspects of the plant DDR is still limited. Important, yet little understood, regulatory factors of the DDR are the long non-coding RNAs (lncRNAs). In humans, 13 lncRNAs functioning in DDR have been characterized to date, whereas no such lncRNAs have been characterized in plants yet. By meta-analysis, we identified the long intergenic non-coding RNA induced by DNA damage (LINDA) that responds strongly to various DNA double-strand break-inducing treatments, but not to replication stress induced by mitomycin C. After DNA damage, LINDA is rapidly induced in an ATM- and SOG1-dependent manner. Intriguingly, the transcriptional response of LINDA to DNA damage is similar to that of its flanking hypothetical protein-encoding gene. Phylogenetic analysis of putative Brassicales and Malvales LINDA homologs indicates that LINDA lncRNAs originate from duplication of a flanking small protein-encoding gene followed by pseudogenization. We demonstrate that LINDA is not only needed for the regulation of this flanking gene, but also for fine-tuning of the DDR after the occurrence of DNA double-strand breaks. Moreover, Δlinda mutant root stem cells are unable to recover from DNA damage, most likely due to hyper-induced cell death.

ORGANISM(S): Arabidopsis thaliana

PROVIDER: GSE239993 | GEO | 2023/08/05

REPOSITORIES: GEO

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Project description:DNA damage response (DDR) is a complex process, essential for cell survival. Especially deleterious type of DNA damage are DNA double-strand breaks (DSB), which can lead to genomic instability and malignant transformation if not repaired correctly. The central player in DSB detection and repair is the ATM kinase which orchestrates the action of several downstream factors. Despite substantial knowledge of DNA repair processes, still several aspects of DNA damage detection and signaling are not fully understood. Recent studies have suggested that long non-coding RNAs (lncRNAs) are involved in DDR. Here, we aimed to identify lncRNAs induced upon DNA damage in an ATM-dependent manner. 7 mRNAs and 10 lncRNAs were significantly induced 1h after ionizing radiation (IR) in healthy donors, whereas none in AT patients. 447 mRNAs and 149 lncRNAs were induced 8h after IR in the control group, while only 100 mRNAs and 3 lncRNAs in AT patients. Among IR-induced mRNAs, we found several genes with well-known functions in DDR. Gene Set Enrichment Analysis and Gene Ontology revealed delayed induction of key DDR pathways in AT patients compared to controls. The induction and dynamics of selected 9 lncRNAs were confirmed by RT-qPCR at several time-points after IR on a larger cohort. Moreover, inhibition of ATM with a specific inhibitor (KU-60019) proved that those lncRNAs are dependent on ATM. Some of the detected lncRNAs are localized next to protein-coding genes involved in DDR. We observed that induction of lncRNAs after IR preceded changes in expression of adjacent genes. This indicates that IR-induced lncRNAs may regulate the transcription of nearby genes. Subcellular fractionation into chromatin, nuclear, and cytoplasmic fractions revealed that the majority of studied lncRNAs are localized in chromatin, which further suggests their role in regulation of gene expression. In summary, our study revealed several lncRNAs induced by IR in an ATM-dependent manner. Their co-localization and co-expression with genes involved in DDR suggest that those lncRNAs may be important players in cellular response to DNA damage.

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The long non-coding RNA LINDA restrains cellular collapse following DNA damage in Arabidopsis thaliana

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