TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control

Douse, Christopher H.; Tchasovnikarova, Iva A.; Timms, Richard T.; Protasio, Anna V.; Seczyńska, Marta; Prigozhin, Daniil M.; Albecka, Anna; Wagstaff, Jane L.; Williamson, James C; Freund, Stefan; Lehner, Paul J.; Modis, Y.

doi:10.1038/s41467-020-18761-6

Cited by 65 publications

(129 citation statements)

References 84 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…In each case, transcriptional epigenetic repression is coupled to the synthesis of a transcript and sometimes to its degradation. The fission yeast RITS complex seems to match well our HUSH model, at least when involved in the RNAi-independent pathway, with yeast Chp1 and Tas3 sharing structural features with TASOR, MPP8 and periphilin, as also noticed recently by Schalch et al and Douse et al 37,42 and with its ability to recruit CNOT1/NOT1 43 , the exosome and MTR4 alike TASOR. In agreement with our data, HUSH targets were shown to be enriched in transcriptionally active chromatin 2,4,42 .…”

supporting

confidence: 86%

See 1 more Smart Citation

TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV

Matkovic

Morel

Larrous

et al. 2020

Preprint

View full text Add to dashboard Cite

The Human Silencing Hub (HUSH) complex constituted of TASOR, MPP8 and Periphilin is involved in the spreading of H3K9me3 repressive marks across genes and transgenes such as ZNF encoding genes, ribosomal DNAs, LINE-1, Retrotransposons and Retroelements or the integrated HIV provirus1–5. The deposit of these repressive marks leads to heterochromatin formation and inhibits gene expression. The precise mechanisms of silencing mediated by HUSH is still poorly understood. Here, we show that TASOR depletion increases the accumulation of transcripts derived from the HIV-1 LTR promoter at a post-transcriptional level. By counteracting HUSH, Vpx from HIV-2 mimics TASOR depletion. With the use of a Yeast-Two-Hybrid screen, we identified new TASOR partners involved in RNA metabolism including the RNA deadenylase CCR4-NOT complex scaffold CNOT1. TASOR and CNOT1 interact in vivo and synergistically repress HIV expression from its LTR. In fission yeast, the RNA-induced transcriptional silencing (RITS) complex presents structural homology with HUSH. During transcription elongation by RNA polymerase II, RITS recruits a TRAMP-like RNA degradation complex composed of CNOT1 partners, MTR4 and the exosome, to ultimately repress gene expression via H3K9me3 deposit. Similarly, we show that TASOR interacts and cooperates with MTR4 and the exosome, in addition to CNOT1. We also highlight an interaction between TASOR and RNA Polymerase II, predominantly under its elongating state, and between TASOR and some HUSH-targeted nascent transcripts. Furthermore, we show that TASOR overexpression facilitates the association of the aforementioned RNA degradation proteins with RNA polymerase II. Altogether, we propose that HUSH operates at the transcriptional and post-transcriptional levels to repress HIV proviral gene expression.

show abstract

supporting

confidence: 86%

“…as also noticed recently by Schalch et al and Douse et al 37,42 and with its ability to recruit 248 CNOT1/NOT1 43 , the exosome and MTR4 alike TASOR. In agreement with our data, 249 HUSH targets were shown to be enriched in transcriptionally active chromatin 2,4,42 .…”

supporting

confidence: 73%

TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV

Matkovic

Morel

Larrous

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…However, we validated that manipulation of the expression of a gene has transcriptomic effects positively correlated with the GCH of that gene [39,40] (iii) At the time, we also had no possibility to perform additional molecular experiments for functional validation of the investigated pathways. However, most of our transcriptomic results (including tumor heterogeneity [70][71][72][73], activation of chemokine [43,44,74] and VEGF [51,75] signaling pathways, major roles of TASOR [76,77] and ALG13 [78]) can explain functional and clinical observations of other authors.…”

Section: Discussionmentioning

confidence: 85%

Genomic Fabric Remodeling in Metastatic Clear Cell Renal Cell Carcinoma (ccRCC): A New Paradigm and Proposal for a Personalized Gene Therapy Approach

Iacobaş

Mgbemena

Iacobaş

et al. 2020

Cancers

View full text Add to dashboard Cite

Published transcriptomic data from surgically removed metastatic clear cell renal cell carcinoma samples were analyzed from the genomic fabric paradigm (GFP) perspective to identify the best targets for gene therapy. GFP considers the transcriptome as a multi-dimensional mathematical object constrained by a dynamic set of expression controls and correlations among genes. Every gene in the chest wall metastasis, two distinct cancer nodules, and the surrounding normal tissue of the right kidney was characterized by three independent measures: average expression level, relative expression variation, and expression correlation with each other gene. The analyses determined the cancer-induced regulation, control, and remodeling of the chemokine and vascular endothelial growth factor (VEGF) signaling, apoptosis, basal transcription factors, cell cycle, oxidative phosphorylation, renal cell carcinoma, and RNA polymerase pathways. Interestingly, the three cancer regions exhibited different transcriptomic organization, suggesting that the gene therapy should not be personalized only for every patient but also for each major cancer nodule. The gene hierarchy was established on the basis of gene commanding height, and the gene master regulators DAPK3,TASOR, FAM27C and ALG13 were identified in each profiled region. We delineated the molecular mechanisms by which TASOR overexpression and ALG13 silencing would selectively affect the cancer cells with little consequences for the normal cells.

show abstract

“…The CLANS clustering analysis also suggests that LRRC9-ART should be regarded as a separate family within the ART-like clan/superfamily. The same applies to the DUF3715 family that was recently shown to possess an ART-like structure ( Douse et al, 2020 ). Representatives of both families clearly cluster away from other ART-like clan members and the two novel families are also away from each other.…”

Section: Resultsmentioning

confidence: 85%

“…The full catalogue of ADP-ribosylation enzymes is likely far from completion, as one may expect from recent discoveries of novel ART domains in effectors from pathogenic bacteria that perform non-canonical ubiquitination ( Akturk et al, 2018 ; Kalayil et al, 2018 ; Kim et al, 2018 ), novel ART/macro pairs in bacterial toxin/antitoxin systems ( Jankevicius et al, 2016 ) and novel human macro domains ( Dudkiewicz & Pawłowski, 2019 ). Other examples of novel ADP-ribosylation players are provided by the viral macro domains, present in many dangerous viruses, including the SARS and SARS-CoV-2 coronaviruses ( Saikatendu et al, 2005 ), and by the recently characterized novel ART-like domain (DUF3715) in the human TASOR protein involved in gene silencing ( Douse et al, 2020 ; Tchasovnikarova et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

A novel predicted ADP-ribosyltransferase-like family conserved in eukaryotic evolution

Wyżewski

Gradowski

Krysińska

et al. 2021

PeerJ

View full text Add to dashboard Cite

The presence of many completely uncharacterized proteins, even in well-studied organisms such as humans, seriously hampers full understanding of the functioning of the living cells. ADP-ribosylation is a common post-translational modification of proteins; also nucleic acids and small molecules can be modified by the covalent attachment of ADP-ribose. This modification, important in cellular signalling and infection processes, is usually executed by enzymes from the large superfamily of ADP-ribosyltransferases (ARTs). Here, using bioinformatics approaches, we identify a novel putative ADP-ribosyltransferase family, conserved in eukaryotic evolution, with a divergent active site. The hallmark of these proteins is the ART domain nestled between flanking leucine-rich repeat (LRR) domains. LRRs are typically involved in innate immune surveillance. The novel family appears as putative novel ADP-ribosylation-related actors, most likely pseudoenzymes. Sequence divergence and lack of clearly detectable “classical” ART active site suggests the novel domains are pseudoARTs, yet atypical ART activity, or alternative enzymatic activity cannot be excluded. We propose that this family, including its human member LRRC9, may be involved in an ancient defense mechanism, with analogies to the innate immune system, and coupling pathogen detection to ADP-ribosyltransfer or other signalling mechanisms.

show abstract

TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control

Cited by 65 publications

References 84 publications

TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV

TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV

Genomic Fabric Remodeling in Metastatic Clear Cell Renal Cell Carcinoma (ccRCC): A New Paradigm and Proposal for a Personalized Gene Therapy Approach

A novel predicted ADP-ribosyltransferase-like family conserved in eukaryotic evolution

Contact Info

Product

Resources

About