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Subtelomeric Transcription and Its Regulation Marta Kwapisz, Antonin Morillon Subtelomeric Transcription and its Regulation Marta Kwapisz, Antonin Morillon To cite this version: Marta Kwapisz, Antonin Morillon. Subtelomeric Transcription and its Regulation. Journal of Molec- ular Biology, Elsevier, 2020, 432 (15), pp.4199-4219. 10.1016/j.jmb.2020.01.026. hal-03065215 HAL Id: hal-03065215 https://hal.archives-ouvertes.fr/hal-03065215 Submitted on 14 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Review Subtelomeric Transcription and its Regulation Marta Kwapisz 1 and Antonin Morillon 2 1 - Laboratoire de Biologie Moleculaire Eucaryote, Centre de Biologie Integrative (CBI), Universite de Toulouse, CNRS, UPS, France 2 - ncRNA, Epigenetic and Genome Fluidity, CNRS UMR 3244, Sorbonne Universite, PSL University, Institut Curie, Centre de Recherche, 26 rue d'Ulm, 75248, Paris, France Correspondence to Antonin Morillon: [email protected]. https://doi.org/10.1016/j.jmb.2020.01.026 Edited by Brian Luke. Abstract The subtelomeres, highly heterogeneous repeated sequences neighboring telomeres, are transcribed into coding and noncoding RNAs in a variety of organisms. Telomereproximal subtelomeric regions produce non- coding transcripts i.e., ARRET, aARRET, subTERRA, and TERRA, which function in telomere maintenance. The role and molecular mechanisms of the majority of subtelomeric transcripts remain unknown. This review depicts the current knowledge and puts into perspective the results obtained in different models from yeasts to humans. © 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). General Overview of long noncoding RNAs (lncRNAs) transcribed into telomeric tracts from promoters embedded in sub- Subtelomeres are regions immediately adjacent to telomeres [20e22]. the telomeric repeats. They consist of repetitions of heterogeneous sequences, and have, therefore, Telomere and subtelomere features been difficult to map and sequence. Only recently has the complete assembly of subtelomeres become Telomeres are nucleoprotein caps protecting possible, thanks to the progress in sequencing chromosome ends from erosion and from DNA techniques, as well as the use of high throughput repair machinery that could recognize them as optical mapping of large single DNA molecules in DNA breaks. Indeed, this could trigger the formation nanochannel arrays [1], [2e6]. While our under- of chromosomal aberrations, such as end-to-end standing of subtelomeric structure and activity is still fusions, which would destabilize the genome. developing, accumulating data support the idea that Telomeres are composed of tandem arrays of short subtelomeres are chromosomal entities with specific double-stranded repeats and a single-stranded 30G- functions. To date, subtelomeres have been overhang [23,24]. Due to the so-called “end-replica- involved in (1) Telomere maintenance and regulation tion problem,” telomeres shorten with each cell of telomere length (in budding yeast [7,8], in fission division [25]. Excluding those in D. melanogaster yeast [9], Plasmodium falciparum and Tetrahymena that are maintained thanks to a retrotransposon [10,11]), (2) Proper chromosome segregation [12], mechanism [26], telomeres in all Eukaryotes are (3) Chromosome recognition and pairing during elongated by telomerase [27,28]. Telomeric repeats meiosis [13], (4) Replicative senescence [14,15], are specifically bound by telomere-binding proteins, (5) Nuclear positioning of telomeres [16], (6) Control which in most organisms are called shelterin com- of spreading of telomeric heterochromatin [14,17]), plex [29]. Moreover, telomeres can fold into different (7) Phenotypic polymorphism and genome plasticity structures, such as the well-known telomeric loop (T- [18,19], and finally, in (8) the regulation of TERRA loop; Fig. 1a[30]) that protects the chromosome transcriptionda telomeric repeat-containing family ends from unwanted fusions. To form this large loop, 0022-2836/© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Journal of Molecular Biology (2020) 432, 4199e4219 4200 Subtelomeric Transcription Fig. 1. Overview of telomeric structures and potential molecular mechanisms of action of telomeric and subtelomeric transcripts. Schematic representation of a chromosome highlighting the telomeres (rainbow squares) at its extremities. Telomeres (in yellow) are composed of tandem repeats bound by shelterin complex and telomerase, which elongates telomeric DNA. TPE intensity decreases toward the centromere. a. Schematic representation of a telomeric t- loop, including a displacement loop (D-loop). b. G-quadruplexes formed on a telomeric 30G-overhang. c. Telomeric R-loop (TRL) constituted by RNAPII-transcribed TERRA and telomeric sequences. Additionally, G-quadruplexes can be formed by a single G-rich strand. d. Schematic DNA loop representing TPE-OLD and other telomere long-range interactions. the single-stranded 30G-overhang invades the of repeated homologous sequences, subtelomeres homologous double-stranded region forming a dis- exhibit the highest instability in the genome [44,45]. placement loop (D-loop [31,32]). The G-rich telo- Various types of large-scale rearrangements shape meric repeats can also generate G-quadruplex subtelomeres, such as segmental duplication ampli- structures (Fig. 1b[33e35]). The most recently fication, the formation of extended tandem repeat discovered telomeric R-loop (TRL) is a three- arrays, and extended deletions (as described for stranded structure that contains a DNA:RNA hybrid humans and plants [2,3,46]). In consequence, implicating TERRA (Fig. 1c). The TRL regulates subtelomeres are highly polymorphic [18,46,47]. telomere length and is instrumental in recombination These allelic variations affect the expression of [36e38]. Telomeres are enriched in heterochromatic coding and noncoding RNAs embedded in or located marks (H3K9me3, H4K20me3, the PRC2-repressive near subtelomeres. mark H3K27me3, DNA methylation, and hetero- Although there is no sequence homology between chromatin protein 1 e HP1; [39e43], which spread subtelomeres of different organisms, their structures through subtelomeric regions by a mechanism called and features are similar [48,49]. In general, they can Telomere Position Effect (TPE). The proper organi- be divided into two domains. The telomere-proximal zation of this heterochromatic domain is important region found immediately adjacent to the telomere is for the maintenance of telomere length through called TAS (Telomere Associated Sequence). TAS regulation of telomerase activity and through recom- is gene-poor and contains homologous blocks of bination (ALT mechanismdalternative lengthening sequences highly conserved across many chromo- of telomeres). some ends [50,51]. The second domain, the The size of subtelomeres varies greatly among telomere-distal region, which is centromere-prox- organisms: ranging from 500 kb in each autosomal imal, contains sequences found at only a few arm in humans, 100 kb in fission yeast to 10 kb in chromosome ends, as well as sequences specific budding yeast. Furthermore, subtelomeres share to a given subtelomeric region [52]. Devoid of little or no homology. Due to the presence of blocks essential genes, telomere-distal regions harbor Subtelomeric Transcription 4201 nonessential genes and multiple gene families higher-order structures (long-distance looping). A [53e55]. Tracts of degenerated telomeric repeats variant of TPE, called TPE-OLD (telomere position often separate these two domains (ITS, internal/ effect over long distance [61]; Fig. 1d), modulates interstitial telomeric sequences) (for general struc- the expression of target genes at any position in the ture see Fig. 2). Furthermore, telomeres and sub- genome by telomere looping [60]. An important telomeres form specialized heterochromatin factor regulating TPE is telomere length. Telomere structures, which are essential for chromosome shortening provokes changes in the protein content stability [17,46,56e58]. Two main mechanisms within telomeres and subtelomeric regions, which, in influence subtelomeric transcription at chromosome turn, become less compacted and loose heterochro- ends, Copy Number Variation (CNV) and Telomeric matin marks. This reduces TPE and TPE-OLD and Position Effect (TPE). CNV modifies the number of leads to the activation of subtelomeric genes [61]. subtelomeric sequences through recombination Telomeric and subtelomeric regions can also form [59]. TPE imposes transcriptional repression of loops of various sizes with more or less distant nearby sequences [60] by changing their chromatin genomic loci. Little is known about these structures state. It operates by histone modifications, a quantity as their existence has only recently been discovered of telomere-associated proteins (cis-spreading), and thanks to chromosome capture methods. Described Fig. 2. Organization
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