DOCSLIB.ORG

Non-Coding RNA: a Protective Role for TERRA at Telomeres

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Non-Coding RNA: a Protective Role for TERRA at Telomeres RESEARCH HIGHLIGHTS Nature Reviews Genetics | Published online 17 Jul 2017; doi:10.1038/nrg.2017.58 Finally, depletion of TERRA NON-CODING RNA led to increased telomerase RNA levels and activity in mouse ES cells, concomitant with an increase in A protective role for telomere dysfunction and defects, indicating a role for TERRA in maintaining telomere integrity. The TERRA at telomeres authors propose that TERRA expres- sion may promote ALT in cancer cells by specifically suppressing From yeast to humans, telomeric Using an in vivo proteomic ATRX and telomerase in this context. DNA is transcribed by RNA poly- approach, the authors used identi- In a second study, Graf et al. merase II into the long non-coding fication of direct RNA interacting focused on yeast cells, in which one (lnc) telomeric repeat-containing proteins (iDRiP) to determine critically short telomere is sufficient RNA (TERRA), but the exact the protein interactome of TERRA. to trigger senescence. It was known functions of this RNA and its mode The analysis identified 134 enriched that in the absence of telomerase, of action have remained poorly proteins belonging to several func- homology-directed repair (HDR) understood. Two studies in Cell now tional groups, including chromatin between sister chromatids can par- reveal a protective role for TERRA at and transcription factors, cell cycle tially compensate telomere shorten- chromosome ends. regulators and DNA replication pro- ing to prevent early-onset senescence. Telomeric DNA is composed teins, as well as proteins involved in Using quantitative PCR (qPCR) of long repetitive sequences with a alternative lengthening of telomeres and DNA–RNA hybrid immunopre- single-stranded 3ʹ overhang several (ALT), a mechanism that relies cipitation (DRIP), the authors could hundred nucleotides in length. The on homologous recombination- show that TERRA accumulates at length of telomeres, which shorten mediated DNA copying to critically short telomeres, forming with every cell division, is maintained counteract telomere shortening. RNA–DNA hybrids (R-loops). by the ribonucleoprotein complex TERRA levels and TERRA R-loops telomerase, the lack of which leads were found to be tightly regulated to progressive telomere shortening through the cell cycle, forming in and activation of the DNA damage marked changes in gene the S phase before telomere replica- response, resulting in irreversible cell expression resulting from tion, before being degraded. Upon cycle arrest (senescence) or cell death. TERRA depletion telomere shortening, however, the To map chromatin regions bound accumulation of TERRA R-loops by TERRA, Chu et al. combined two leads to the activation of the DNA established methods, chromatin iso- ALT has previously been associ- damage response, which promotes lation by RNA purification (ChIRP) ated with mutations in the chromatin HDR, thereby protecting against and capture hybridization analysis of remodeller α-thalassaemia/mental premature senescence. RNA targets (CHART), to develop a retardation syndrome X-linked Taken together, the two studies new approach they call CHIRT-seq, (ATRX) both in vitro and in several provide pivotal insights into the which identified thousands of bind- human cancers, where it is activated regulatory function of TERRA in ing sites in mouse embryonic stem to promote telomere lengthening in mice and yeast. Given the essential (ES) cells. RNA fluorescence in situ the absence of telomerase. Chu et al. role of telomeres for maintaining hybridization (FISH) also showed observed that ATRX colocalized genome integrity, and the detrimen- that TERRA was not restricted with TERRA in vivo. Moreover, the tal impact of telomere crisis (a state to telomeres. proteins were found to share a subset of extensive genome instability) Functional effects of TERRA were of target genes, displaying antag- in cancer, it will be interesting to Macmillan Publishers Limited assessed through antisense oligo­ onistic effects on gene expression, determine how far these novel nucleotide-mediated degradation of with TERRA promoting and ATRX findings translate to humans. the lncRNA in vivo, and successful suppressing gene expression of both Linda Koch depletion was confirmed by RNA- telomeric and non-telomeric targets. ORIGINAL ARTICLES Chu, H.-P. et al. TERRA RNA FISH and northern blot analysis. In vitro and in vivo analyses showed antagonizes ATRX and protects telomeres. Cell Transcriptomic analysis showed further that TERRA modulates ATRX 170, 86–101 (2017) | Graf, M. et al. Telomere length marked changes in gene expression distribution and competes with determines TERRA and R-loop regulation through the cell cycle. Cell 170, 72–85 (2017) resulting from TERRA depletion. telomeric DNA for ATRX binding. NATURE REVIEWS | GENETICS www.nature.com/nrg ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. .
Load more

Recommended publications
  • ATRX Protects Cells Against Replication-Induced Genomic Instability
    ATRX Protects Cells Against Replication-Induced Genomic Instability Danton Ivanochko M.Sc. Thesis This thesis is submitted to the Faculty of Graduate and Postdoctoral Studies in partial fulfillment of the requirements for the degree of Master of Science in Biochemistry with a specialization in Human and Molecular Genetics Department of Biochemistry, Microbiology, and Immunology Faculty of Medicine University of Ottawa, Ontario, Ontario, Canada © Danton Ivanochko, Ottawa, Canada, 2016 Dedicated to my parents. ii Abstract Expansive proliferation of neural progenitor cells (NPCs) is a prerequisite to the temporal waves of neuronal differentiation that generate the six-layered cerebral cortex. NPC expansion places a heavy burden on proteins that regulate chromatin packaging and genome integrity, which is further reflected by the growing number of developmental disorders caused by mutations in chromatin regulators. Accordingly, mutations in ATRX, a chromatin remodelling protein required for heterochromatin maintenance at telomeres and simple repeats, cause the ATR-X syndrome. Here, we demonstrate that proliferating ATRX-null cells accumulate DNA damage, while also exhibiting sensitivity to hydroxyurea-induced replication fork stalling. Specifically, PARP1 hyperactivation and replication-dependent double strand DNA breakage indicated replication fork protection defects, while DNA fiber assays confirmed that ATRX was required to protect replication forks from degradation. Interestingly, inhibition of the exonuclease MRE11 by the small molecule mirin could prevent degradation. Thus, ATRX is required to limit replication stress during NPC expansion. iii Acknowledgements First and foremost, I would like to thank my supervisor, Dr. David Picketts, for his guidance and support during my undergraduate and graduate studies. Thanks to the members of my thesis advisory committee, Dr.
    [Show full text]
  • Functional Characterization of the TERRA Transcriptome at Damaged Telomeres
    ARTICLE Received 16 Apr 2014 | Accepted 25 Sep 2014 | Published 31 Oct 2014 DOI: 10.1038/ncomms6379 Functional characterization of the TERRA transcriptome at damaged telomeres Antonio Porro1,2,w, Sascha Feuerhahn1,2,*,w, Julien Delafontaine1,3,*, Harold Riethman4, Jacques Rougemont1,3 & Joachim Lingner1,2 Telomere deprotection occurs during tumorigenesis and aging upon telomere shortening or loss of the telomeric shelterin component TRF2. Deprotected telomeres undergo changes in chromatin structure and elicit a DNA damage response (DDR) that leads to cellular senescence. The telomeric long noncoding RNA TERRA has been implicated in modulating the structure and processing of deprotected telomeres. Here, we characterize the human TERRA transcriptome at normal and TRF2-depleted telomeres and demonstrate that TERRA upregulation is occurring upon depletion of TRF2 at all transcribed telomeres. TRF2 represses TERRA transcription through its homodimerization domain, which was previously shown to induce chromatin compaction and to prevent the early steps of DDR activation. We show that TERRA associates with SUV39H1 H3K9 histone methyltransferase, which promotes accumulation of H3K9me3 at damaged telomeres and end-to-end fusions. Altogether our data elucidate the TERRA landscape and defines critical roles for this RNA in the telomeric DNA damage response. 1 Ecole Polytechnique Fe´de´rale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland. 2 Swiss Institute for Experimental Cancer Research (ISREC) at EPFL, Station 19, CH-1015 Lausanne, Switzerland. 3 Bioinformatics and Biostatistics Core Facility, EPFL and Swiss Institute of Bioinformatics, Station 15, CH-1015 Lausanne, Switzerland. 4 The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA. * These authors contributed equally to this work.
    [Show full text]
  • Telomeres in ICF Syndrome Cells Are Vulnerable to DNA Damage Due to Elevated DNA:RNA Hybrids
    ARTICLE Received 14 Jul 2016 | Accepted 21 Nov 2016 | Published 24 Jan 2017 DOI: 10.1038/ncomms14015 OPEN Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids Shira Sagie1, Shir Toubiana1,*, Stella R. Hartono2,*, Hagar Katzir1, Aya Tzur-Gilat1, Shany Havazelet1, Claire Francastel3, Guillaume Velasco3,Fre´de´ric Che´din2 & Sara Selig1 DNA:RNA hybrids, nucleic acid structures with diverse physiological functions, can disrupt genome integrity when dysregulated. Human telomeres were shown to form hybrids with the lncRNA TERRA, yet the formation and distribution of these hybrids among telomeres, their regulation and their cellular effects remain elusive. Here we predict and confirm in several human cell types that DNA:RNA hybrids form at many subtelomeric and telomeric regions. We demonstrate that ICF syndrome cells, which exhibit short telomeres and elevated TERRA levels, are enriched for hybrids at telomeric regions throughout the cell cycle. Telomeric hybrids are associated with high levels of DNA damage at chromosome ends in ICF cells, which are significantly reduced with overexpression of RNase H1. Our findings suggest that abnormally high TERRA levels in ICF syndrome lead to accumulation of telomeric hybrids that, in turn, can result in telomeric dysfunction. 1 Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel. 2 Department of Molecular and Cellular Biology and Genome Center, University of California, Davis, California 95616, USA. 3 Universite´ Paris Diderot, Sorbonne Paris Cite´, Epigenetics and Cell Fate, CNRS UMR7216, Paris Cedex 75205, France. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to S.
    [Show full text]
  • Patient Mutations Alter ATRX Targeting to PML Nuclear Bodies
    European Journal of Human Genetics (2008) 16, 192–201 & 2008 Nature Publishing Group All rights reserved 1018-4813/08 $30.00 www.nature.com/ejhg ARTICLE Patient mutations alter ATRX targeting to PML nuclear bodies Nathalie G Be´rube´1,3,4, Jasmine Healy1,4, Chantal F Medina1, Shaobo Wu1, Todd Hodgson1, Magdalena Jagla1 and David J Picketts*,2 1Molecular Medicine Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada; 2Departments of Medicine and Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada ATRX is a SWI/SNF-like chromatin remodeling protein mutated in several X-linked mental retardation syndromes. Gene inactivation studies in mice demonstrate that ATRX is an essential protein and suggest that patient mutations likely retain partial activity. ATRX associates with the nuclear matrix, pericentromeric heterochromatin, and promyelocytic leukemia nuclear bodies (PML-NBs) in a speckled nuclear staining pattern. Here, we used GFP–ATRX fusion proteins to identify the specific domains of ATRX necessary for subnuclear targeting and the effect of patient mutations on this localization. We identified two functional nuclear localization signals (NLSs) and two domains that target ATRX to nuclear speckles. One of the latter domains is responsible for targeting ATRX to PML-NBs. Surprisingly, this domain encompassed motifs IV–VI of the SNF2 domain suggesting that in addition to chromatin remodeling, it may also have a role in subnuclear targeting. More importantly, four different patient mutations within this domain resulted in an B80% reduction in the number of transfected cells with ATRX nuclear speckles and PML colocalization. These results demonstrate that patient mutations have a dramatic effect on subnuclear targeting to PML-NBs.
    [Show full text]
  • X-Linked Diseases: Susceptible Females
    REVIEW ARTICLE X-linked diseases: susceptible females Barbara R. Migeon, MD 1 The role of X-inactivation is often ignored as a prime cause of sex data include reasons why women are often protected from the differences in disease. Yet, the way males and females express their deleterious variants carried on their X chromosome, and the factors X-linked genes has a major role in the dissimilar phenotypes that that render women susceptible in some instances. underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the Genetics in Medicine (2020) 22:1156–1174; https://doi.org/10.1038/s41436- heart, blood, skin, muscle, and bones. Summarized here are many 020-0779-4 examples of the different presentations in males and females. Other INTRODUCTION SEX DIFFERENCES ARE DUE TO X-INACTIVATION Sex differences in human disease are usually attributed to The sex differences in the effect of X-linked pathologic variants sex specific life experiences, and sex hormones that is due to our method of X chromosome dosage compensation, influence the function of susceptible genes throughout the called X-inactivation;9 humans and most placental mammals – genome.1 5 Such factors do account for some dissimilarities. compensate for the sex difference in number of X chromosomes However, a major cause of sex-determined expression of (that is, XX females versus XY males) by transcribing only one disease has to do with differences in how males and females of the two female X chromosomes. X-inactivation silences all X transcribe their gene-rich human X chromosomes, which is chromosomes but one; therefore, both males and females have a often underappreciated as a cause of sex differences in single active X.10,11 disease.6 Males are the usual ones affected by X-linked For 46 XY males, that X is the only one they have; it always pathogenic variants.6 Females are biologically superior; a comes from their mother, as fathers contribute their Y female usually has no disease, or much less severe disease chromosome.
    [Show full text]
  • A Practical Qpcr Approach to Detect TERRA, the Elusive Telomeric Repeat-Containing RNA ⇑ Marianna Feretzaki, Joachim Lingner
    Methods xxx (2016) xxx–xxx Contents lists available at ScienceDirect Methods journal homepage: www.elsevier.com/locate/ymeth A practical qPCR approach to detect TERRA, the elusive telomeric repeat-containing RNA ⇑ Marianna Feretzaki, Joachim Lingner Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland article info abstract Article history: Telomeres, the heterochromatic structures that protect the ends of the chromosomes, are transcribed into Received 27 May 2016 a class of long non-coding RNAs, telomeric repeat-containing RNAs (TERRA), whose transcriptional reg- Received in revised form 1 August 2016 ulation and functions are not well understood. The identification of TERRA adds a novel level of structural Accepted 7 August 2016 and functional complexity at telomeres, opening up a new field of research. TERRA molecules are Available online xxxx expressed at several chromosome ends with transcription starting from the subtelomeric DNA proceed- ing into the telomeric tracts. TERRA is heterogeneous in length and its expression is regulated during the Keywords: cell cycle and upon telomere damage. Little is known about the mechanisms of regulation at the level of Telomeres transcription and post transcription by RNA stability. Furthermore, it remains to be determined to what Subtelomeres TERRA extent the regulation at different chromosome ends may differ. We present an overview on the method- Transcriptional regulation ology of how RT-qPCR and primer pairs that are specific for different subtelomeric sequences can be used qRT-PCR to detect and quantify TERRA expressed from different chromosome ends. Ó 2016 Published by Elsevier Inc.
    [Show full text]
  • Expression and Differential Regulation of Human TERRA at Several Chromosome Ends
    Downloaded from rnajournal.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Expression and differential regulation of human TERRA at several chromosome ends Marianna Feretzaki,1,2 Patricia Renck Nunes,1,2 and Joachim Lingner1 1 Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland 2 Equal contribution *Corresponding author: [email protected] Running head: TERRA expression from several chromosome ends Keywords: TERRA, long noncoding RNA, telomeres, telomere length Feretzaki 1 Downloaded from rnajournal.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press ABSTRACT The telomeric long noncoding RNA TERRA has been implicated in regulating telomere maintenance by telomerase and homologous recombination, and in influencing telomeric protein composition during the cell cycle and the telomeric DNA damage response. TERRA transcription starts at subtelomeric regions resembling the CpG islands of eukaryotic genes extending towards chromosome ends. TERRA contains chromosome specific subtelomeric sequences at its 5’ end and long tracts of UUAGGG-repeats towards the 3’ end. Conflicting studies have been published to whether TERRA is expressed from one or several chromosome ends. Here, we quantify TERRA species by RT-qPCR in normal and several cancerous human cell lines. By using chromosome specific subtelomeric DNA primers we demonstrate that TERRA is expressed from a large number of telomeres. Deficiency in DNA methyltransferases leads to TERRA upregulation only at the subset of chromosome ends that contain CpG-island sequences revealing differential regulation of TERRA promoters by DNA methylation. However, independently of the differences in TERRA expression, short telomeres were uniformly present in a DNA methyltransferase deficient cell line indicating that telomere length was not dictated by TERRA expression in cis.
    [Show full text]
  • Heterochromatin: Guardian of the Genome
    CB34CH08_Karpen ARI 16 July 2018 12:50 Annual Review of Cell and Developmental Biology Heterochromatin: Guardian of the Genome Aniek Janssen,1,2,∗ Serafin U. Colmenares,1,2,∗ and Gary H. Karpen1,2 1Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA; email: [email protected] 2Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA Annu. Rev. Cell Dev. Biol. 2018. 34:8.1–8.24 Keywords The Annual Review of Cell and Developmental constitutive heterochromatin, pericentromeres, genome stability, Biology is online at cellbio.annualreviews.org chromosome segregation, repetitive DNA, DNA repair https://doi.org/10.1146/annurev-cellbio-100617- 062653 Abstract Copyright c 2018 by Annual Reviews. Constitutive heterochromatin is a major component of the eukaryotic nu- All rights reserved cleus and is essential for the maintenance of genome stability. Highly concen- ∗ These authors contributed equally. trated at pericentromeric and telomeric domains, heterochromatin is riddled with repetitive sequences and has evolved specific ways to compartmentalize, Annu. Rev. Cell Dev. Biol. 2018.34. Downloaded from www.annualreviews.org silence, and repair repeats. The delicate balance between heterochromatin Access provided by University of California - Berkeley on 09/14/18. For personal use only. epigenetic maintenance and cellular processes such as mitosis and DNA re- pair and replication reveals a highly dynamic and plastic chromatin domain that can be perturbed by multiple mechanisms, with far-reaching conse- quences for genome integrity. Indeed, heterochromatin dysfunction pro- vokes genetic turmoil by inducing aberrant repeat repair, chromosome- segregation errors, transposon activation, and replication stress and is strongly implicated in aging and tumorigenesis.
    [Show full text]
  • Structure of the SWI2/SNF2 Chromatin-Remodeling Domain of Eukaryotic Rad54
    ARTICLES Structure of the SWI2/SNF2 chromatin-remodeling domain of eukaryotic Rad54 Nicolas H Thomä1, Bryan K Czyzewski1,2, Andrei A Alexeev3, Alexander V Mazin4, Stephen C Kowalczykowski3 & Nikola P Pavletich1,2 SWI2/SNF2 chromatin-remodeling proteins mediate the mobilization of nucleosomes and other DNA-associated proteins. SWI2/SNF2 proteins contain sequence motifs characteristic of SF2 helicases but do not have helicase activity. Instead, they couple ATP hydrolysis with the generation of superhelical torsion in DNA. The structure of the nucleosome-remodeling domain of zebrafish Rad54, a protein http://www.nature.com/nsmb involved in Rad51-mediated homologous recombination, reveals that the core of the SWI2/SNF2 enzymes consist of two ␣/␤-lobes similar to SF2 helicases. The Rad54 helicase lobes contain insertions that form two helical domains, one within each lobe. These insertions contain SWI2/SNF2-specific sequence motifs likely to be central to SWI2/SNF2 function. A broad cleft formed by the two lobes and flanked by the helical insertions contains residues conserved in SWI2/SNF2 proteins and motifs implicated in DNA-binding by SF2 helicases. The Rad54 structure suggests that SWI2/SNF2 proteins use a mechanism analogous to helicases to translocate on dsDNA. Cellular processes such as transcription, replication, DNA repair and breaks by Rad51-mediated homologous recombination15–20. Like other recombination require direct access to DNA. This process is facilitated SWI2/SNF2 remodeling enzymes, Rad54 can translocate on DNA, gen- by the SWI2/SNF2 family of ATPases, which detach DNA from histones erate superhelical torsion and enhance the accessibility to nucleosomal and other bound proteins1,2. The SWI2/SNF2 chromatin remodeling DNA18,19,21.
    [Show full text]
  • ATRX-Mutant Cancers to WEE1 Inhibition Junbo Liang1, Hong Zhao2,3, Bill H
    Published OnlineFirst September 24, 2019; DOI: 10.1158/0008-5472.CAN-18-3374 CANCER RESEARCH | TRANSLATIONAL SCIENCE Genome-Wide CRISPR-Cas9 Screen Reveals Selective Vulnerability of ATRX-Mutant Cancers to WEE1 Inhibition Junbo Liang1, Hong Zhao2,3, Bill H. Diplas4, Song Liu5, Jianmei Liu2,3, Dingding Wang1, Yan Lu1, Qing Zhu6, Jiayu Wu1, Wenjia Wang1, Hai Yan4, Yi-Xin Zeng6, Xiaoyue Wang1, and Yuchen Jiao2,7 ABSTRACT ◥ The tumor suppressor gene ATRX is frequently mutated in a induced apoptosis. AZD1775 also selectively inhibited the prolif- variety of tumors including gliomas and liver cancers, which are eration of patient-derived primary cell lines from gliomas with highly unresponsive to current therapies. Here, we performed a naturally occurring ATRX mutations, indicating that the synthetic genome-wide synthetic lethal screen, using CRISPR-Cas9 genome lethal relationship between WEE1 and ATRX could be exploited in a editing, to identify potential therapeutic targets specific for ATRX- broader spectrum of human tumors. As WEE1 inhibitors have been mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell investigated in several phase II clinical trials, our discovery provides lines engineered for ATRX loss, we identified 58 genes, including the the basis for an easily clinically testable therapeutic strategy specific checkpoint kinase WEE1, uniquely required for the cell growth of for cancers deficient in ATRX. ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell Significance: ATRX-mutant cancer cells depend on WEE1, lines in vitro, as well as xenografts in vivo. The increased sensitivity which provides a basis for therapeutically targeting WEE1 in to the WEE1 inhibitor was caused by accumulated DNA damage– ATRX-deficient cancers.
    [Show full text]
  • ATRX and RECQ5 Define Distinct Homologous Recombination Subpathways
    ATRX and RECQ5 define distinct homologous recombination subpathways Amira Elbakrya, Szilvia Juhásza,1, Ki Choi Chana, and Markus Löbricha,2 aRadiation Biology and DNA Repair, Technical University of Darmstadt, 64287 Darmstadt, Germany Edited by Stephen C. West, The Francis Crick Institute, London, United Kingdom, and approved December 10, 2020 (received for review May 25, 2020) Homologous recombination (HR) is an important DNA double- or by the resolvase GEN1 which induce asymmetrical or sym- strand break (DSB) repair pathway that copies sequence informa- metrical incisions in the two strands at each HJ, giving rise to tion lost at the break site from an undamaged homologous tem- both crossover (CO) and non-CO products (6–8). Additionally, plate. This involves the formation of a recombination structure dHJs can be dissolved by the BLM/TOPOIIIα/RMI1/2 (BTR) that is processed to restore the original sequence but also harbors complex, where the two HJs migrate toward each other and the potential for crossover (CO) formation between the participat- merge to form a hemicatenane that is then decatenated by top- ing molecules. Synthesis-dependent strand annealing (SDSA) is an oisomerases, thus separating the two molecules without ex- HR subpathway that prevents CO formation and is thought to change of genetic material (9–11). Under specific circumstances, predominate in mammalian cells. The chromatin remodeler ATRX a third subpathway termed break-induced replication (BIR) can promotes an alternative HR subpathway that has the potential to mediate conservative DNA synthesis initiated by the D-loop to form COs. Here, we show that ATRX-dependent HR outcompetes copy the entire chromosome arm (12, 13).
    [Show full text]
  • Structure Specific Recognition of Telomeric Repeats Containing RNA
    4492–4506 Nucleic Acids Research, 2020, Vol. 48, No. 8 Published online 4 March 2020 doi: 10.1093/nar/gkaa134 Structure specific recognition of telomeric repeats containing RNA by the RGG-box of hnRNPA1 Meenakshi Ghosh 1 and Mahavir Singh 1,2,* 1Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, 560012, India and 2NMR Research Centre, Indian Institute of Science, Bengaluru, 560012, India Received April 12, 2019; Revised February 12, 2020; Editorial Decision February 19, 2020; Accepted February 21, 2020 Downloaded from https://academic.oup.com/nar/article/48/8/4492/5780085 by guest on 25 September 2021 ABSTRACT mation, and replication (4,5). TERRA RNA repeats have been found to bind a number of proteins that include telom- The telomere repeats containing RNA (TERRA) is erase reverse transcriptase (hTERT), telomeric repeat bind- transcribed from the C-rich strand of telomere DNA ing factor-2 (TRF2) and heterogenous nuclear ribonucleo- and comprises of UUAGGG nucleotides repeats in protein A1 (hnRNPA1) (6,7). Complexity of TERRA func- humans. The TERRA RNA repeats can exist in single tions also stems from the observation that TERRA re- stranded, RNA-DNA hybrid and G-quadruplex forms peats can exist in single-stranded, RNA-DNA hybrid, and in the cell. Interaction of TERRA RNA with hnRNPA1 RNA G-quadruplex forms in the cell (8). The G-quadruplex has been proposed to play critical roles in mainte- forms can further exist in structures of different topologies nance of telomere DNA. hnRNPA1 contains an N- with intramolecular G-quadruplex being the most physio- terminal UP1 domain followed by an RGG-box con- logically relevant form.
    [Show full text]