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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Expression of subtelomeric lncRNAs links telomeres maintenance with RNA decay in S. cerevisiae

ABSTRACT: Long non-coding RNAs (lncRNAs) have been shown to regulate gene expression, chromatin domains and chromosome stability in eukaryotic cells. Recent observations have reported the existence of telomere associated long ncRNAs (TERRA, telomeric repeat containing RNA) in mammalian and yeast cells but their function(s) remain(s) poorly characterized. Here, we report the existence in S. cerevisiae of several sense and antisense Cryptic Unstable Transcripts (CUTs) and Xrn1-sensitive Unstable Transcripts (XUT) initiating within the subtelomeric repeated region Y’. We show that the Y’ ncRNAs, subTERRA, are distinct from TERRA and are mainly destabilized by the general cytoplasmic and nuclear 5’- and 3’- RNA decays in a sense-dependent manner. subTERRA transcription is mainly sustained by RNAPII and subTERRA accumulate preferentially during the G1/S transition and in C-terminal rap1 mutants independently of Rap1p function in silencing. The accumulation of subTERRA in RNA decay mutants coincides with telomere misregulation: shortening of telomere length, loss of telomeric clustering in mitotic cells, indicating that subTERRA might compete with factors involved in telomere elongation, tethering and/or clustering. We propose that subtelomeric RNAs expression links telomere maintenance with RNA degradation pathways. Exmination of two yeast mutants for RNA decay.

ORGANISM(S): Saccharomyces cerevisiae

SUBMITTER: Marc Descrimes

PROVIDER: E-GEOD-67585 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression of subtelomeric lncRNAs links telomeres maintenance with RNA decay in S. cerevisiae

Project description:Long non-coding RNAs (lncRNAs) have been shown to regulate gene expression, chromatin domains and chromosome stability in eukaryotic cells. Recent observations have reported the existence of telomere associated long ncRNAs (TERRA, telomeric repeat containing RNA) in mammalian and yeast cells but their function(s) remain(s) poorly characterized. Here, we report the existence in S. cerevisiae of several sense and antisense Cryptic Unstable Transcripts (CUTs) and Xrn1-sensitive Unstable Transcripts (XUT) initiating within the subtelomeric repeated region Y’. We show that the Y’ ncRNAs, subTERRA, are distinct from TERRA and are mainly destabilized by the general cytoplasmic and nuclear 5’- and 3’- RNA decays in a sense-dependent manner. subTERRA transcription is mainly sustained by RNAPII and subTERRA accumulate preferentially during the G1/S transition and in C-terminal rap1 mutants independently of Rap1p function in silencing. The accumulation of subTERRA in RNA decay mutants coincides with telomere misregulation: shortening of telomere length, loss of telomeric clustering in mitotic cells, indicating that subTERRA might compete with factors involved in telomere elongation, tethering and/or clustering. We propose that subtelomeric RNAs expression links telomere maintenance with RNA degradation pathways.

2015-04-30 | GSE67585 | GEO

Subtelomeric p53 Binding Prevents Accumulation of DNA Damage at Human Telomeres

Project description:Telomeres and tumor suppressor protein TP53 (p53) function in genome protection, but a direct role of p53 at telomeres has not yet been described. Here, we have identified non-canonical p53 binding sites within the human subtelomeres that suppress the accumulation of DNA damage at telomeric repeat DNA. These non-canonical subtelomeric p53 binding sites conferred transcription enhancer-like functions that include an increase in local histone H3K9 and H3K27 acetylation and stimulation of subtelomeric transcripts, including telomere-repeat containing RNA (TERRA). p53 suppressed formation of telomere-associated Î³H2AX and prevented telomere DNA degradation in response to DNA damage stress. Our findings indicate that p53 provides a direct chromatin-associated protection to human telomeres, as well as other fragile genomic sites. We propose that p53-associated chromatin modifications enhance local DNA repair or protection to provide a previously unrecognized tumor suppressor function of p53. p53 binding was analyzed by ChIP-Seq in HCT116 cells treated with camptothecin or untreated control.

2016-01-07 | E-GEOD-75528 | biostudies-arrayexpress

TERRA RNA antagonizes ATRX and protects telomeres

Project description:Through an integration of genomic and proteomic approaches to advance understanding of long noncoding RNAs, we investigate the function of the telomeric transcript, TERRA. By identifying thousands of TERRA target sites in the mouse genome, we demonstrate that TERRA can bind both in cis to telomeres and in trans to genic targets. We then define a large network of interacting proteins, including epigenetic factors, telomeric proteins, and the RNA helicase, ATRX. TERRA and ATRX share hundreds of target genes and are functionally antagonistic at these loci: whereas TERRA activates, ATRX represses gene expression. At telomeres, TERRA competes with telomeric DNA for ATRX binding, suppresses ATRX localization, and ensures telomeric stability. Depleting TERRA increases telomerase activity and induces telomeric pathologies, including formation of telomere-induced DNA damage foci and loss or duplication of telomeric sequences. We conclude that TERRA functions as an epigenomic modulator in trans and as an essential regulator of telomeres in cis.

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Subtelomeric p53 Binding Prevents Accumulation of DNA Damage at Human Telomeres

Project description:Telomeres and tumor suppressor protein TP53 (p53) function in genome protection, but a direct role of p53 at telomeres has not yet been described. Here, we have identified non-canonical p53 binding sites within the human subtelomeres that suppress the accumulation of DNA damage at telomeric repeat DNA. These non-canonical subtelomeric p53 binding sites conferred transcription enhancer-like functions that include an increase in local histone H3K9 and H3K27 acetylation and stimulation of subtelomeric transcripts, including telomere-repeat containing RNA (TERRA). p53 suppressed formation of telomere-associated γH2AX and prevented telomere DNA degradation in response to DNA damage stress. Our findings indicate that p53 provides a direct chromatin-associated protection to human telomeres, as well as other fragile genomic sites. We propose that p53-associated chromatin modifications enhance local DNA repair or protection to provide a previously unrecognized tumor suppressor function of p53.

2016-01-07 | GSE75528 | GEO

PAR-TERRA RNA directs homologous sex chromosome pairing

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Expression data by telomere elongation in xenograft.

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2015-02-05 | E-GEOD-56177 | biostudies-arrayexpress

Mammalian telomeres reforged with non-telomeric sequences

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Target enrichment followed by high throughput sequencing of telomeric DDRNAs in telomere-deprotected mouse cells

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2017-05-10 | GSE86964 | GEO

TERRA interactome in human ALT cancer cells identified by iDRiP-MS method

Project description:Alternative Lengthening of Telomeres (ALT) cancer cells are a subset of cancers that depend on the homologous recombination mechanism to extend their telomere length independent of telomerase. ALT cells contain elevated levels of the telomeric-repeat containing long noncoding RNA (TERRA), which is an RNA transcribed by RNA polymerase II and can form RNA:DNA (R-loops) hybrids at telomeres. Lines of evidence have shown that the formation of R-loops at telomeres could be one of the mechanisms to trigger DNA repair to lengthen telomeres. We perform iDRiP-MS, a method to capture specific RNA interacting protein by UV light crosslinking using antisense probe capture (Chu et al., 2017a; Minajigi et al., 2015), to explore the TERRA interactomes in human ALT cancer cell. Our TERRA interactome data reveals that TERRA interacts with an extensive subset of DNA repair proteins in ALT cells including the endonuclease XPF, suggesting that TERRA R-loops activate DDR via XPF to promote homologous recombination and telomere replication to drive ALT.

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ZBTB48 is both a vertebrate telomere-binding protein and a transcriptional activator

Project description:Telomeres constitute the ends of linear chromosomes and together with the shelterin complex form a structure essential for genome maintenance and stability. In addition to the constitutive binding of the shelterin complex, other direct, yet more transient interactions are mediated by the CST complex and HOT1, while subtelomeric variant repeats are recognized by NR2C/F transcription factors. Recently, the Kruppel-like zinc finger protein ZBTB48 has been described as a novel telomere-associated factor in the vertebrate lineage. Here, we show that ZBTB48 binds directly both to telomeric as well as to subtelomeric variant repeat sequences. ZBTB48 is found at telomeres of human cancer cells regardless of the mode of telomere maintenance and it acts as a negative regulator of telomere length. In addition to its telomeric function, we demonstrate through a combination of RNAseq, ChIPseq and expression proteomics experiments that ZBTB48 acts as a transcriptional activator on a small set of target genes, including mitochondrial fission process 1 (MTFP1). This discovery places ZBTB48 at the interface of telomere length regulation, transcriptional control and mitochondrial metabolism.

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