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Article
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Regulation of meiotic telomere dynamics through membrane fluidity promoted by AdipoR2-ELOVL2
Meiosis is a specialized cell division for generating germ cells. The authors show that the lipid composition in the cellular membrane influences meiosis-specific chromosomal dynamics in mouse testis.
- Jingjing Zhang
- , Mario Ruiz
- & Hiroki Shibuya
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| Open Access
TERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells
Here the authors show that the telomere repeat-containing RNA (TERRA) undergoes phase separation with the lysine-specific demethylase 1A (LSD1) to promote R-loop formation for homology-directed telomere DNA synthesis in the alternative lengthening of telomere (ALT) pathway.
- Meng Xu
- , Dulmi Senanayaka
- & Huaiying Zhang
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| Open Access
ZNF524 directly interacts with telomeric DNA and supports telomere integrity
ZNF524 is a newly described protein that binds to telomeres, the ends of linear chromosomes. ZNF524 promotes the presence of two members of the shelterin complex, TRF2/RAP1, at telomeres, and prevents genomic instability.
- Hanna Braun
- , Ziyan Xu
- & Dennis Kappei
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Unzipped chromosome-level genomes reveal allopolyploid nematode origin pattern as unreduced gamete hybridization
The occurrence and consequences of polyploidization in clonally reproducing animals is unclear. Here, the authors generate 4 polyploid Meloidogyne genomes, identifying a telomeric element, resolving genome structures and extensive chromosome fusion events, and revealing origin patterns.
- Dadong Dai
- , Chuanshuai Xie
- & Ming Sun
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Article
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Pathway choice in the alternative telomere lengthening in neoplasia is dictated by replication fork processing mediated by EXD2’s nuclease activity
Here the authors demonstrate that remodelling of perturbed replication forks by the exonuclease EXD2 modulates pathway choice within the Alternative Lengthening of Telomeres mechanism and identify potentially clinically important synthetic lethal interactions in ALT cancer cells.
- Ronan Broderick
- , Veronica Cherdyntseva
- & Wojciech Niedzwiedz
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Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance
Alternative lengthening of telomeres (ALT) provides cancer cells a mechanism to sustain replicative immortality. Here, the authors identify KDM2A as a molecular vulnerability in ALT-dependent cancer cells and demonstrate its role in the resolution of ALT-specific telomere clusters via recruitment of SENP6.
- Fei Li
- , Yizhe Wang
- & Hongwu Zheng
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The RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression
Monoallelic VSG expression is essential for Trypanosoma brucei survival. Competition between TbRAP1’s RNA and dsDNA binding activities ensures that TbRAP1 sustains a high level expression of the active VSG while silencing other VSGs globally.
- Amit Kumar Gaurav
- , Marjia Afrin
- & Bibo Li
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Telomere length associates with chronological age and mortality across racially diverse pulmonary fibrosis cohorts
The association of telomere length with age and mortality across racially diverse pulmonary fibrosis populations is unknown. Here, the authors show that leukocyte telomere length associates with chronologic age and is predictive of mortality in pulmonary fibrosis across racial groups.
- Ayodeji Adegunsoye
- , Chad A. Newton
- & Imre Noth
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A non-genetic switch triggers alternative telomere lengthening and cellular immortalization in ATRX deficient cells
Mutations of ATRX are frequent in cancers that immortalize through the ALT (Alternative lengthening of telomeres) pathway. Here the authors show that ALT features are repressed in embryonic stem cells that lack ATRX but induced by continuous telomere instability triggered upon cell differentiation.
- Timothy K. Turkalo
- , Antonio Maffia
- & Dirk Hockemeyer
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High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform
There exist challenges in quantifying the length of individual telomeres at single nucleotide resolution. Here the authors report a method to capture telomeres and accurately analyse their length in human cell lines and patient peripheral blood leukocyte samples using single-molecule real-time sequencing.
- Cheng-Yong Tham
- , LaiFong Poon
- & Shang Li
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| Open Access
Consequences of telomere dysfunction in fibroblasts, club and basal cells for lung fibrosis development
Telomere dysfunction induced by TRF1 depletion in fibroblasts, club and basal cells did not lead to interstitial lung fibrosis, underscoring alveolar type II cells as the relevant cell type in pulmonary fibrosis.
- Sergio Piñeiro-Hermida
- , Paula Martínez
- & Maria A. Blasco
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Article
| Open Access
XPF activates break-induced telomere synthesis
Here the authors show TERRA R-loops recruit the endonuclease XPF to telomeres, leading to DNA double-strand breaks to activate break-induced telomere synthesis at telomeres that utilize the alternative lengthening of telomeres (ALT) pathway to extend their telomeres independent of telomerase.
- Chia-Yu Guh
- , Hong-Jhih Shen
- & Hsueh-Ping Catherine Chu
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Article
| Open Access
DAXX-ATRX regulation of p53 chromatin binding and DNA damage response
The tumor suppressor proteins DAXX and ATRX are frequently mutated in cancers with alternative lengthening of telomeres (ALT). This study shows that DAXX-ATRX regulates p53 chromatin accessibility and DNA damage response and that disruption of this pathway is critical for ALT cell survival.
- Nitish Gulve
- , Chenhe Su
- & Paul. M. Lieberman
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TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance
Telomerase protects chromosome ends in stem cells and cancer cells. Here the authors show that Trimethylguaonsine Synthase 1 (TGS-1) – dependent trimethylguanosine capping of the RNA component of the human telomerase complex has an important role in directing telomere dependent telomere maintenance and suppressing the ALT pathway in cancer cells.
- Valentina Buemi
- , Odessa Schillaci
- & Stefan Schoeftner
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| Open Access
The methyl phosphate capping enzyme Bmc1/Bin3 is a stable component of the fission yeast telomerase holoenzyme
There exists a remarkable evolutionary breadth of telomerase holoenzyme components among eukaryotes. Here the authors report that the fission yeast methyl phosphate capping enzyme Bin3/Bmc1 regulates telomerase activity by promoting holoenzyme formation.
- Jennifer Porat
- , Moaine El Baidouri
- & Mark A. Bayfield
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A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis
Most eukaryotes maintain telomeres using a specialized reverse transcriptase. Here the authors report that Thc1 (Telomerase Holoenzyme Component 1) and Bmc1 (Bin3/MePCE 1) form a complex with Pof8, a constitutive member of telomerase in fission yeast.
- Diego J. Páez-Moscoso
- , David V. Ho
- & Peter Baumann
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| Open Access
Hematopoiesis under telomere attrition at the single-cell resolution
The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. Here the authors demonstrate that hematopoietic stem cells with short telomeres induced by mutations affecting telomerase complex genes undergo differentiation towards megakaryopoiesis through the activation of the IFI16-mediated interferon response.
- Natthakan Thongon
- , Feiyang Ma
- & Simona Colla
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Article
| Open Access
Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres
Mammalian shelterin proteins POT1 and TPP1 form a stable heterodimer that protects telomere ends. The authors exploit the observation that mice have two POT1 paralogs, enabling functional dissections to shed important light on the mechanistic basis for human POT1 functions.
- Peili Gu
- , Shuting Jia
- & Sandy Chang
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RPA shields inherited DNA lesions for post-mitotic DNA synthesis
Single-stranded DNA during DNA replication and repair in S/G2 needs protection by replication protein A (RPA). Here the authors reveal that RPA also shields inherited single-stranded DNA in G1, representing replication remnants from the previous cell cycle, to allow for post-mitotic DNA synthesis.
- Aleksandra Lezaja
- , Andreas Panagopoulos
- & Matthias Altmeyer
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TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
TERRA RNA has previously been linked to Alternative lengthening of telomeres (ALT). Here the authors developed a tool to rapidly inhibit TERRA transcription from different chromosome ends in an ALT cell line to show that TERRA transcription actively promotes break induced replication (BIR) and destabilizes telomere integrity in ALT cells.
- Bruno Silva
- , Rajika Arora
- & Claus M. Azzalin
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BRCA1 binds TERRA RNA and suppresses R-Loop-based telomeric DNA damage
BRCA1-mediated resolution of R-loops has previously been described. Here the authors reveal a functional association of BRCA1 with TERRA RNA at telomeres, which develops in an R-loop-, and a cell cycle-dependent manner.
- Jekaterina Vohhodina
- , Liana J. Goehring
- & David M. Livingston
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| Open Access
Mechanism of MRX inhibition by Rif2 at telomeres
Different proteins localised at telomeres ensure chromosome end stability to prevent double strand-end break recognition. Here the authors provide new insight into how in S. cerevisiae the interaction between Rif2 and Rad50 inhibits MRX functions at telomeres.
- Florian Roisné-Hamelin
- , Sabrina Pobiega
- & Stéphane Marcand
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The double-stranded DNA-binding proteins TEBP-1 and TEBP-2 form a telomeric complex with POT-1
Telomeres, tandem repeats at the ends of linear chromosomes, have evolved to deal with the end replication and end protection. Using a proteomics approach, the authors identify TEBP-1 and TEBP-2, two double-stranded binding proteins which together are required for fertility. Despite being paralogs, they have distinct individual effects on telomere dynamics; TEBP-1 and TEBP-2 are part of a telomeric complex also containing POT-1.
- Sabrina Dietz
- , Miguel Vasconcelos Almeida
- & Falk Butter
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| Open Access
Mutations inhibiting KDM4B drive ALT activation in ATRX-mutated glioblastomas
Alternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilised in 15% of cancers that have been associated with mutations in ATRX. Here the authors reveal a functional role of histone demethylases KDM4B in regulating ALT activation.
- M. Udugama
- , L. Hii
- & L. H. Wong
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| Open Access
Structural variant evolution after telomere crisis
Telomere crisis has been shown to induce chromothripsis and breakage fusion bridge (BFB) cycles in vitro. Here, the authors show that telomere crisis generates a much broader spectrum of structural variations, implying that cancers without chromothripsis and BFB cycles could have emerged from telomere crisis.
- Sally M. Dewhurst
- , Xiaotong Yao
- & Marcin Imieliński
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| Open Access
Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening
Minichromosome maintenance protein 10 (MCM10) is critical for eukaryotic DNA replication. Here, by modelling MCM10 variants in human cell lines, the authors reveal a mechanism of MCM10-associated disease, finding that loss of MCM10 function constrains telomerase activity.
- Ryan M. Baxley
- , Wendy Leung
- & Anja-Katrin Bielinsky
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| Open Access
Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells
Telomeres can be maintained by a telomerase-independent mechanism called an alternative lengthening of telomeres (ALT). Here the authors use mouse Terc (telomerase RNA) knockout embryonic cells and provide longitudinal analysis of ALT telomeres maintained with non-telomeric sequences.
- Chuna Kim
- , Sanghyun Sung
- & Junho Lee
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Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation
Pyruvate kinase phosphorylates histone H3T11 (H3pT11) and represses gene expression by forming a large complex SESAME (Serine-responsive SAM-containing Metabolic Enzyme). Here the authors show that SESAME-catalyzed H3pT11 regulates telomere silencing by promoting Sir2 binding at telomeres and preventing autophagy-mediated Sir2 degradation.
- Shihao Zhang
- , Xilan Yu
- & Shanshan Li
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| Open Access
Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres
~15% of cancers induce alternative lengthening of telomeres (ALT) to activate telomere maintenance. Here, the authors reveal that infection with Kaposi’s sarcoma herpesvirus (KSHV) induces acquisition of ALT-like features in previously non-ALT cell lines.
- Timothy P. Lippert
- , Paulina Marzec
- & Simon J. Boulton
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Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly
Primary microcephaly is a clinical feature of several human telomere disorder syndromes. Here the authors reveal a role of Microcephalin 1 in promoting telomere replication and repair.
- Alessandro Cicconi
- , Rekha Rai
- & Sandy Chang
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Article
| Open Access
Mechanisms of telomerase inhibition by oxidized and therapeutic dNTPs
Telomerase enzymes add telomeric repeats to the end of linear chromosomes. Here the authors reveal mechanisms by which oxidized dNTPs and therapeutic dNTPs inhibit telomerase-mediated telomere elongation.
- Samantha L. Sanford
- , Griffin A. Welfer
- & Patricia L. Opresko
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| Open Access
Persistent telomere cohesion protects aged cells from premature senescence
Telomere function is regulated by the telomere repeat binding proteins TRF1 and TRF2. Here the authors show that decreased levels of TRF1 proteins at shortened telomeres in aged human cells results in persistent telomere cohesion, protecting from premature senescence.
- Kameron Azarm
- , Amit Bhardwaj
- & Susan Smith
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| Open Access
Stability and nuclear localization of yeast telomerase depend on protein components of RNase P/MRP
Pop1 and 6 are subunits of RNase P and RNase MRP, which process ribosomal and tRNAs. The authors show that when Pop1 and 6 are impaired, the telomerase subunit Est1 binds telomerase RNA at normal levels, but the binding is unstable. As a result, nuclear import of the telomerase holoenzyme is inhibited.
- P. Daniela Garcia
- , Robert W. Leach
- & Virginia A. Zakian
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Components of the ribosome biogenesis pathway underlie establishment of telomere length set point in Arabidopsis
Major effect loci controlling natural, heritable variation in telomere length are not known. Here, the authors use QTL mapping and transgenic manipulations in Arabidopsis to implicate the rRNA-processing genes NOP2A and RPL5 in telomere length set point regulation in this model species.
- Liliia R. Abdulkina
- , Callie Kobayashi
- & Eugene V. Shakirov
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Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome
Hutchinson–Gilford progeria syndrome causes premature aging. Here the authors show that activation of the DNA damage response at dysfunctional telomeres and transcription of telomeric non-coding RNAs contributes to the pathogenesis, which can be ameliorated by treatment with sequence-specific telomeric antisense oligonucleotides.
- Julio Aguado
- , Agustin Sola-Carvajal
- & Fabrizio d’Adda di Fagagna
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| Open Access
CSL controls telomere maintenance and genome stability in human dermal fibroblasts
Conversion of dermal fibroblasts into Cancer Associated Fibroblasts (CAFs) can play an important role in keratinocyte tumour development. Here the authors reveal that CSL plays a role in maintenance of telomeres and genomic integrity in both dermal fibroblasts and CAFs.
- Giulia Bottoni
- , Atul Katarkar
- & G. Paolo Dotto
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| Open Access
Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies
Shortening of leukocyte telomere length (LTL) is associated with age and increased risk for various chronic diseases. Here, the authors report genome-wide association studies for LTL in Singaporean Chinese populations and find that longer LTL associates with less severe outcomes of respiratory disease phenotypes.
- Rajkumar Dorajoo
- , Xuling Chang
- & Chew-Kiat Heng
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Article
| Open Access
FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
In cancer cells, telomeres can be elongated through homology directed-repair pathways in a process known as Alternative Lengthening of Telomeres (ALT). Here, the authors reveal that FANCM regulates ALT activity and ALT cell proliferation by limiting the activity of uncontrolled BLM and telomeric R-loops.
- Bruno Silva
- , Richard Pentz
- & Claus M. Azzalin
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Article
| Open Access
SFPQ and NONO suppress RNA:DNA-hybrid-related telomere instability
LncRNA TERRA forms RNA-DNA hybrids at telomere sites leading to telomere instability. Here the authors identify the RNA interacting factors NONO and SFPQ as proteins that interact with TERRA and telomere chromatin and reveal putative roles for these factors in telomere integry maintenance by interfering with RNA:DNA hybrid formation.
- Eleonora Petti
- , Valentina Buemi
- & Stefan Schoeftner
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Article
| Open Access
The H/ACA complex disrupts triplex in hTR precursor to permit processing by RRP6 and PARN
Telomerase RNA (hTR) is transcribed as a 3′-extended precursor. Here the authors examine the processing of hTR precursors of various lengths and show that processing occurs in distinct steps involving different nucleases PARN and RRP6.
- Chi-Kang Tseng
- , Hui-Fang Wang
- & Peter Baumann
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Article
| Open Access
Local enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection
Chromatin dynamics is thought to play an important role in the maintenance of telomeres, yet how has remained poorly understood. Here the authors locally enrich heterochromatin protein 1α (HP1α) at human telomeres to provide insights into the crosstalk between epigenetic regulations and structural dynamics at the telomeres.
- Tracy T. Chow
- , Xiaoyu Shi
- & Elizabeth H. Blackburn
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Article
| Open Access
Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1
Incessant telomere synthesis in cancer cells depends on specific mutations in the TERT promoter, enabling its activation by transcription factors ETS1 and p52. Here, the authors elucidate the structural basis for p52/ETS1 binding to mutant TERT, suggesting a general mechanism for TERT reactivation in cancer.
- Xueyong Xu
- , Yinghui Li
- & Haiwei Song
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Article
| Open Access
CTC1-STN1 terminates telomerase while STN1-TEN1 enables C-strand synthesis during telomere replication in colon cancer cells
The human CST complex (CTC1-STN1-TEN1) is essential for telomere homeostasis. Here the authors dissect the roles of individual CST subunits in telomere length maintenance through regulation of telomerase-mediated G-strand synthesis and DNA polymerase-mediated C-strand synthesis in colon cancer cells.
- Xuyang Feng
- , Shih-Jui Hsu
- & Carolyn M. Price
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Article
| Open Access
HuR regulates telomerase activity through TERC methylation
Mutations in the RNA component TERC can cause telomerase dysfunction but the underlying mechanisms are largely unknown. Here, the authors show that RNA-binding protein HuR regulates telomerase function by enhancing the methylation of TERC, which is impaired by several disease-relevant TERC mutations.
- Hao Tang
- , Hu Wang
- & Wengong Wang
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Article
| Open Access
The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma
Glioblastoma can be classified based on IDH and TERT promoter mutations, but ~20% of glioblastoma do not have these mutations (TERTpWT-IDHWT glioblastoma). Here, the authors present a genetic landscape of TERTpWT-IDHWT glioblastoma, identifying a telomerase-positive subgroup driven by TERT-structural rearrangements and an ALT-positive subgroup with mutations in ATRX or SMARCAL1.
- Bill H. Diplas
- , Xujun He
- & Hai Yan
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Article
| Open Access
TERRA recruitment of polycomb to telomeres is essential for histone trymethylation marks at telomeric heterochromatin
Long non-coding RNA TERRAs are essential for telomere protection and telomere length maintenance. Here the authors report a role for TERRAs in telomeric heterochromatin formation by recruiting Polycomb Repressive Complex 2 to telomeres.
- Juan J. Montero
- , Isabel López-Silanes
- & Maria A. Blasco
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Article
| Open Access
LARP7-like protein Pof8 regulates telomerase assembly and poly(A)+TERRA expression in fission yeast
A functional telomerase complex requires that the catalytic TERT subunit be assembled with the template RNA TER1. Here the authors show that Pof8, a possible LARP7 family protein, is required for assembly of the telomerase complex, and repression of lncRNA transcripts at telomeres in S. pombe.
- Amanda K. Mennie
- , Bettina A. Moser
- & Toru M. Nakamura
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Article
| Open Access
Pof8 is a La-related protein and a constitutive component of telomerase in fission yeast
The core of the telomerase holoenzyme is composed of the reverse transcriptase and the non-coding RNA template. Here the authors identify Pof8 as a new constitutive component of fission yeast telomerase, loss of which causes telomerase assembly defects and critically short telomeres.
- Diego J. Páez-Moscoso
- , Lili Pan
- & Peter Baumann
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Article
| Open Access
LARP7 family proteins have conserved function in telomerase assembly
The telomerase holoenzyme is minimally composed of the reverse transcriptase and the RNA template. Here the authors identify Lar7 as a member of the full complex that helps to stabilise it and protect telomerase RNA from degradation.
- Laura C. Collopy
- , Tracy L. Ware
- & Kazunori Tomita
PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress