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Expression data by G-quadruplex (G4) forming oligonucleotides transfection in 3D culture.

ABSTRACT: Telomere erosion causes cell mortality, suggesting that longer telomeres allow greater number of cell division. In telomerase-positive human cancer cells, however, telomeres are often kept shorter than the surrounding normal tissues. Recently, we have shown that telomere elongation in cancer cells represses innate immune genes and promotes their differentiation in vivo. This implies that short telomeres contribute to cancer malignancy, but it is unclear how such genetic repression is caused by long telomeres. Here we report that telomeric repeat-containing RNA (TERRA) induces genome-wide alteration of gene expression in telomere-elongated cancer cells in vivo. Using three different cell lines, we found that G4 forming oligonucleotide repressed innate immune genes in vivo 3D culture conditions. Most of the suppressed genes belonged to innate immune system categories and were upregulated in various cancers. We propose that TERRA G4 counteracts cancer malignancy through suppression of innate immune genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE56239 | GEO | 2015/02/05

SECONDARY ACCESSION(S): PRJNA242680

REPOSITORIES: GEO

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Expression data by G-quadruplex (G4) forming oligonucleotides transfection in 3D culture.

Project description:Telomere erosion causes cell mortality, suggesting that longer telomeres allow greater number of cell division. In telomerase-positive human cancer cells, however, telomeres are often kept shorter than the surrounding normal tissues. Recently, we have shown that telomere elongation in cancer cells represses innate immune genes and promotes their differentiation in vivo. This implies that short telomeres contribute to cancer malignancy, but it is unclear how such genetic repression is caused by long telomeres. Here we report that telomeric repeat-containing RNA (TERRA) induces genome-wide alteration of gene expression in telomere-elongated cancer cells in vivo. Using three different cell lines, we found that G4 forming oligonucleotide repressed innate immune genes in vivo 3D culture conditions. Most of the suppressed genes belonged to innate immune system categories and were upregulated in various cancers. We propose that TERRA G4 counteracts cancer malignancy through suppression of innate immune genes. Six samples are G4 oligo-transfected cells (PC-3/(uuaggg)^4, PC-3/AS1411, HBC4/(uuaggg)^4, HBC4/AS1411, MKN74/(uuaggg)^4 and MKN74/AS1411), and the other six samples are control oligo-transfected cells.

2015-02-05 | E-GEOD-56239 | biostudies-arrayexpress

Expression data by telomere elongation in xenograft.

Project description:Telomere erosion causes cell mortality, suggesting that longer telomeres allow greater number of cell division. In telomerase-positive human cancer cells, however, telomeres are often kept shorter than the surrounding normal tissues. Recently, we have shown that telomere elongation in cancer cells represses innate immune genes and promotes their differentiation in vivo. This implies that short telomeres contribute to cancer malignancy, but it is unclear how such genetic repression is caused by long telomeres. Here we report that telomeric repeat-containing RNA (TERRA) induces genome-wide alteration of gene expression in telomere-elongated cancer cells in vivo. Using three different cell lines, we found that telomere elongation upregulates TERRA and downregulates innate immune genes in vivo xenograft tumors. Most of the suppressed genes belonged to innate immune system categories and were upregulated in various cancers. We propose that TERRA G4 counteracts cancer malignancy through suppression of innate immune genes. Four samples are telomere-elongated cells (PC3/LhTERTL, PC3/LhTERTL/cre, HBC4/hTERT and MKN74/hTERT), and the other four samples are control cell lines.

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

Expression data by telomere elongation in xenograft.

Project description:Telomere erosion causes cell mortality, suggesting that longer telomeres allow greater number of cell division. In telomerase-positive human cancer cells, however, telomeres are often kept shorter than the surrounding normal tissues. Recently, we have shown that telomere elongation in cancer cells represses innate immune genes and promotes their differentiation in vivo. This implies that short telomeres contribute to cancer malignancy, but it is unclear how such genetic repression is caused by long telomeres. Here we report that telomeric repeat-containing RNA (TERRA) induces genome-wide alteration of gene expression in telomere-elongated cancer cells in vivo. Using three different cell lines, we found that telomere elongation upregulates TERRA and downregulates innate immune genes in vivo xenograft tumors. Most of the suppressed genes belonged to innate immune system categories and were upregulated in various cancers. We propose that TERRA G4 counteracts cancer malignancy through suppression of innate immune genes.

2015-02-05 | GSE56177 | 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.

2022-09-28 | PXD028882 | Pride

HLTF Prevents G4 Accumulation and Promotes G4-induced Fork Slowing to Maintain Genome Stability

Project description:G-quadruplexes (G4s) form throughout the genome and influence important cellular processes, but their deregulation can challenge DNA replication fork progression and threaten genome stability. Here, we demonstrate an unexpected, dual role for the dsDNA translocase HLTF in G4 metabolism. First, we find that HLTF is enriched at G4s in the human genome and suppresses G4 accumulation throughout the cell cycle using its ATPase activity. This function of HLTF affects telomere maintenance by restricting alternative lengthening of telomeres, a process stimulated by G4s. We also show that HLTF and MSH2, a mismatch repair factor that binds G4s, act in independent pathways to suppress G4s and to promote resistance to G4 stabilization. In a second, distinct role, HLTF restrains DNA synthesis upon G4 stabilization by suppressing PrimPol-dependent repriming. Together, the dual functions of HLTF in the G4 response prevent DNA damage and potentially mutagenic replication to safeguard genome stability.

2024-08-13 | GSE247967 | GEO

Npl3 stabilizes R-loops at telomeres to prevent accelerated replicative senescence

Project description:Telomere shortening rates must be regulated to prevent premature replicative senescence. TERRA R-loops become stabilized at critically short telomeres to promote their elongation through homology-directed repair (HDR), thereby counteracting senescence onset. Using a non-bias proteomic approach to identify telomere binding factors, we identified Npl3, an RNA-binding protein previously implicated in multiple RNA biogenesis processes. Using Chromatin- and RNA immunoprecipitation, we demonstrate that Npl3 interacts with TERRA and telomeres. Furthermore, we show that Npl3 associates to telomeres in an R-loop dependent manner, as changes in R-loop levels, e.g. at short telomeres, modulate the recruitment of Npl3 to chromosome ends. Through a series of genetic and biochemical approaches we demonstrate that Npl3 binds to TERRA and stabilizes R-loops at short telomeres, which in turn promotes HDR and prevents premature replicative senescence onset. This may have implications for diseases associated with excessive telomere shortening.

2020-01-31 | PXD016772 | Pride

RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA

Project description:Alternative lengthening of telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in subsets of highly aggressive cancer. Recent studies have revealed that TERRA (telomere repeat-containing RNA) acts to initiate ALT-associated HDR (ALT-HDR). Here we report that RAD51AP1, a crucial ALT factor, interacts with TERRA and utilizes it to generate D- and R- loop HR intermediates. We also show that RAD51AP1 binds to and may generate and potentially stabilize TERRA-containing R-loops as RAD51AP1 depletion reduces R-loop formation at telomere DNA breaks. Proteomic analyses uncover a new role for RAD51AP1 mediated TERRA R-loop homeostasis in a mechanism of chromatin-directed suppression of TERRA and prevention of transcription-replication collisions during ALT-HDR. Intriguingly, we find that both TERRA binding and this non-canonical function of RAD51AP1 require its intrinsic SUMO-SIM regulatory axis. These findings provide new insights into the multi-contextual functions of RAD51AP1 within the ALT mechanism and regulation of TERRA.

2024-01-26 | PXD035943 | Pride

m6A RNA modification of TERRA lncRNA drives R-Loop formation and is required for telomere maintenance in ALT tumors [II]

Project description:Telomerase-negative tumors can maintain telomere length by alternative lengthening of telomeres (ALT) but the mechanism of telomere maintenance in ALT cells is not well understood. A significant portion of the relapse Neuroblastoma (NB) tumors are positive for ALT which suggests better dissecting the ALT mechanism could provide novel therapeutic opportunities. TERRA RNA which is derived from the telomere ends is localized to telomeres in R-loop dependent manner and is essential for telomere maintenance. In the present study, we provide evidence that RNA modification at the N6 position of internal adenosine (m6A) in TERRA RNA by methyl transferase METTL3 is essential for telomere maintenance in ALT cells and loss of TERRA m6A/METTL3 leads to accumulation of DNA damage over telomere. Our data suggest that m6A modification in TERRA RNA is required for R-loop formation and telomere targeting of TERRA. We observed that R-loop enriched TERRA is abundantly m6A modified and m6A mediated recruitment of hnRNPA2B1 to TERRA RNA is essential for R-loop formation. Together our study suggests that m6A-mediated R-loop formation could be a widespread mechanism utilized by other chromatin-interacting lncRNAs. We also show treating ALT positive NB cells with small molecule METTL3 inhibitor leads to compromised telomere targeting of TERRA and accumulation of DNA damage over telomere, suggesting METTL3 inhibition could be a therapeutic opportunity for ALT positive NB.

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m6A RNA modification of TERRA lncRNA drives R-Loop formation and is required for telomere maintenance in ALT tumors [I]

2023-12-13 | GSE219146 | GEO