Cytosolic RNA:DNA Duplexes Generated by Endogenous Reverse Transcriptase Activity as Autonomous Inducers of Skin Inflammation in Psoriasis

Molès, Jeàn-Pierre; Griez, Anthony; Guilhou, Jean‐Jacques; Girard, C.; Nagot, Nicolas; Perre, Philippe Van de; Dujols, Pierre

doi:10.1371/journal.pone.0169879

Cited by 11 publications

(10 citation statements)

References 50 publications

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“…This can lead to a pro-inflammatory state, involving the activation of TLR pathways 33 , 34 . A recent study reports the presence cytosolic RNA:DNA duplexes in psoriatic lesions generated by endogenous reverse transcriptases, which can contribute to exceeding the tolerance for cyDNAs in keratinocytes and therefore play a role in the disease initiation 35 . We report a ~1.4-fold upregulation of two members of HERV-K family (HERV-K11d and HERV-K14c) encoding reverse transcriptase genes in lesional skin compared to unlesional skin of psoriasis patients.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional landscape of human endogenous retroviruses (HERVs) and other repetitive elements in psoriatic skin

Lättekivi

Kõks

Keermann

et al. 2018

Sci Rep

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Human endogenous retrovirus (HERV) sequences make up at least 8% of the human genome. Transcripts originating from these loci as well as proteins encoded by them have been detected in various tissues. HERVs are believed to be implicated in autoimmune diseases, however the extent to which, has remained unclear. Differential expression studies have so far been limited to certain HERV subfamilies with conserved sequences. No studies have been published describing the genome-wide expression pattern of HERVs and repetitive elements in the context of psoriasis. In the present study, we analysed total RNA sequencing data from skin samples of 12 psoriasis patients and 12 healthy controls, which enabled us to describe the entire transcriptional landscape of repetitive elements. We report high levels of repetitive element expression in the skin of psoriasis patients as well as healthy controls. The majority of differentially expressed elements were downregulated in lesional and non-lesional skin, suggesting active HERV suppression in the pro-inflammatory environment of psoriatic skin. However, we also report upregulation of a small subset of HERVs previously described in the context of autoimmune diseases, such as members of the HERV-K and W families, with the potential to affect the immunopathogenesis of psoriasis.

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Section: Discussionmentioning

confidence: 99%

Transcriptional landscape of human endogenous retroviruses (HERVs) and other repetitive elements in psoriatic skin

Lättekivi

Kõks

Keermann

et al. 2018

Sci Rep

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“…RNAseH2C mutations) that lead the accumulation of RNA:DNA hybrids causes early-onset inflammatory diseases (fatal auto-inflammatory diseases), and are likely linked to the pathogenesis of age-related auto-immune diseases (e.g. systemic lupus erythematosus and psoriasis) [12,13]. Current literature is concordant in considering that degradation of misplaced RNA:DNA hybrids is a crucial physiologic phenomenon to preserve normal cell functioning [12].…”

mentioning

confidence: 99%

Genomic stability, anti-inflammatory phenotype, and up-regulation of the RNAseH2 in cells from centenarians

et al. 2019

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Longevity is tightly linked across evolution to the maintenance of genomic stability. Centenarians are long-living subjects who reach the extreme limits of human lifespan, while escaping the inflammatory age-related diseases. Current literature underpins that genomic damage elicits inflammation by engaging cytoplasmic sensors via the misplacement of nucleic acids (including RNA:DNA hybrids) outside the nucleus. Here, we report that high genomic stability (i.e. preserved telomere length) and blunted DNA-damage-induced inflammation characterize centenarian's fibroblasts. This molecular make-up is associated with reduced amounts of cytoplasmic RNA:DNA hybrids. These cells convey high levels of the RNA:DNA degrading enzyme subunit RNAseH2C, whose knock-down up-regulates inflammatory mediators. The RNAseH2C locus is hypomethylated in centenarian's cells, hyper-methylated in senescent cells, and in atherosclerotic plaques and cancer tissues. Noteworthy, RNAseH2C expression and anti-inflammatory phenotype can be elicited in different cell types exposed to Extracellular Vesicles isolated from centenarian's cell cultures. These data provide evidence on the molecular mechanisms that allow centenarians to escape the deleterious effects of inflamm-aging and to avoid inflammatory age-related diseases.Running title: RNAseH2-driven genomic stability in centenarians

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“…In addition to S9.6 antibodies, RNA:DNA hybrids can be detected by using the RNase H1 N-terminal hybrid-binding domain (HDB), which can even recognize stretches made up by just four ribonucleotides [182]. Finally, D5H6 is another antibody able to react with RNA:DNA hybrids [183,184], even if less efficiently, compared to the other systems. Independently of the used tools, treatment with RNase H1 is then essential to prove that the signal obtained is specific for RNA:DNA hybrids.…”

Section: Stretches Of Rnmps Hybridized With Dnamentioning

confidence: 99%

“…Indications about the abundance and localization of RNA:DNA hybrids can also be obtained by immunofluorescence studies. The S9.6 antibody has been extensively used for this purpose [183,188], while Aguilera and colleagues used the HBD of RNase H1 fused with the green fluorescent protein (GFP), forming the so-called HB-GFP [188]. Both these strategies led to the identification of RNA:DNA hybrids in the nucleus of cells, with high intensities detected in the nucleolar region (where the majority of R-loops are formed [117]), as well as in the cytoplasm, possibly because of the abundant RNA:DNA hybrids present in mitochondria.…”

Section: Stretches Of Rnmps Hybridized With Dnamentioning

confidence: 99%

One, No One, and One Hundred Thousand: The Many Forms of Ribonucleotides in DNA

Nava

Grasso

Sertic

et al. 2020

IJMS

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In the last decade, it has become evident that RNA is frequently found in DNA. It is now well established that single embedded ribonucleoside monophosphates (rNMPs) are primarily introduced by DNA polymerases and that longer stretches of RNA can anneal to DNA, generating RNA:DNA hybrids. Among them, the most studied are R-loops, peculiar three-stranded nucleic acid structures formed upon the re-hybridization of a transcript to its template DNA. In addition, polyribonucleotide chains are synthesized to allow DNA replication priming, double-strand breaks repair, and may as well result from the direct incorporation of consecutive rNMPs by DNA polymerases. The bright side of RNA into DNA is that it contributes to regulating different physiological functions. The dark side, however, is that persistent RNA compromises genome integrity and genome stability. For these reasons, the characterization of all these structures has been under growing investigation. In this review, we discussed the origin of single and multiple ribonucleotides in the genome and in the DNA of organelles, focusing on situations where the aberrant processing of RNA:DNA hybrids may result in multiple rNMPs embedded in DNA. We concluded by providing an overview of the currently available strategies to study the presence of single and multiple ribonucleotides in DNA in vivo.

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Cytosolic RNA:DNA Duplexes Generated by Endogenous Reverse Transcriptase Activity as Autonomous Inducers of Skin Inflammation in Psoriasis

Cited by 11 publications

References 50 publications

Transcriptional landscape of human endogenous retroviruses (HERVs) and other repetitive elements in psoriatic skin

Transcriptional landscape of human endogenous retroviruses (HERVs) and other repetitive elements in psoriatic skin

Genomic stability, anti-inflammatory phenotype, and up-regulation of the RNAseH2 in cells from centenarians

One, No One, and One Hundred Thousand: The Many Forms of Ribonucleotides in DNA

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