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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Chia Yu Guh

LAB HEAD: Hsueh-Ping Chu

PROVIDER: PXD028882 | Pride | 2022-09-28

REPOSITORIES: Pride

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			Action	DRS
	2018-0727_lncRNA-TMT-F1.msf	Msf
	2018-0727_lncRNA-TMT-F1.raw	Raw
	2018-0727_lncRNA-TMT-F2.msf	Msf
	2018-0727_lncRNA-TMT-F2.raw	Raw
	2018-0727_lncRNA-TMT-F3.msf	Msf

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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.

2023-12-13 | GSE219212 | GEO

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

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

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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

Functional characterization of the TERRA transcriptome at damaged telomeres

Project description:We characterize the TERRA transcriptome at normal and TRF2-depleted telomeres by RNA-seq and we demonstrate that TERRA upregulation is occurring at all transcribed telomeres upon depletion of TRF2. RNA-sequencing of HeLa mRNA, 4 samples: with or without TERRA enrichment by IP (respectively "IP" and "input"), with or without TFR-2 knock-down (respectively "_T" and "_EV").

2014-10-31 | E-GEOD-56727 | biostudies-arrayexpress

HIRA protects telomeres against R-loop-induced instability in ALT cancer cells [ATAC-seq]

Project description:Alterations to chromatin modifiers, such as the inactivating mutations in the ATRX-DAXX chromatin remodeling/histone H3.3 deposition complex, are implicated as drivers of the cancer-specific Alternative Lengthening of Telomeres (ALT) pathway. Prior studies revealed that HIRA adapts to compensate for ATRX-DAXX loss to sustain ALT cancer cell survival. However, the specific mechanisms underlying HIRA’s ability to rescue telomeres from the consequences of ATRX-DAXX loss remain unclear. Here, using ATAC-seq and CUT&RUN, we demonstrate that HIRA-mediated deposition of new H3.3 is essential to maintain chromatin accessibility and to prevent the detrimental accumulation of nucleosome-free single-stranded DNA (ssDNA) at telomeres in ATRX-deficient ALT cancer cells. We provide evidence that the timely deposition of new H3.3 by HIRA and interacting partners UBN1 and UBN2 is crucial to prevent unwarranted TERRA R-loop formation and transcription-replication conflicts (TRCs) at telomeres. Furthermore, we determined that the delivery of H3.3 to telomeric chromatin by HIRA may link the phosphorylation of an H3.3-specific amino acid, serine 31, by Chk1 with mechanisms that promote productive ALT. Therefore, these studies identify a role for HIRA-mediated histone H3.3 deposition in TERRA R-loop homeostasis that we propose is essential for ensuring the survival of ALT cancer cells where the ATRX-DAXX complex is activated.

2024-10-21 | GSE269268 | GEO

HIRA protects telomeres against R-loop-induced instability in ALT cancer cells [CUT&RUN]

2024-10-21 | GSE269261 | GEO

Expression of telomerase prevents ALT and maintains telomeric heterochromatin in juvenile brain tumors.

Project description:The up-regulation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape dysfunctional telomeres, senescence and apoptosis. Paediatric brain tumors frequently exhibit Alternative Lengthening of Telomere (ALT) as active TMM, but the mechanisms involved in the induction of ALT in brain tumor cells are not clear. Here, we report a model of juvenile zebrafish brain tumor that progressively develops ALT. We discovered that reduced expression of tert and increase in Terra expression precedes ALT development. Additionally, tumors show persistent telomeric DNA damage and loss of heterochromatin marks. Comparative analysis of gene expression after the rescue of ALT with telomerase and analysis of telomerase positive paediatric brain cancers showed normalization of telomeric heterochromatin and maintenance of telomere length, with reduced expression of genes of the pre-replicative complex as hallmark. Thus our study identifies telomere maintenance mechanisms as major drivers of DNA replication and chromatin status at telomeres in brain cancers.

2022-07-01 | GSE134135 | GEO

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

RNA-DNA hybrids prevent resection at dysfunctional telomeres

Project description:At critically short telomeres TERRA RNA-DNA hybrids become stabilized and drive homology-directed repair (HDR) to delay replicative senescence. However, even at long- and intermediate-length telomeres, not subject to HDR, transient TERRA RNA-DNA hybrids form, suggestive of additional roles. Here, we report that hybrids at telomeres prevent resection by the Exo1 nuclease when telomeres become non-functional. We employed the well-characterized cdc13-1 allele, where telomere resection can be induced in a temperature dependent manner, to demonstrate that ssDNA generation at telomeres is either prevented or augmented when RNA-DNA hybrids are stabilized or destabilized, respectively. The viability of cdc13-1 cells is affected by the presence or absence of hybrids accordingly. These results give insights into an additional role of TERRA at dysfunctional telomeres suggesting that it not only affects replicative senescence rates through HDR activation at critically short telomeres, but may also affect resection rates at intermediate length telomeres in pre-senescent cells.

2023-01-18 | PXD034986 | Pride

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