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Solving the Telomere Replication Problem

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Solving the Telomere Replication Problem G C A T T A C G G C A T genes Review Solving the Telomere Replication Problem Laetitia Maestroni, Samah Matmati and Stéphane Coulon * Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe labélisée Ligue Contre le Cancer, 13273 Marseille, France; [email protected] (L.M.); [email protected] (S.M.) * Correspondence: [email protected]; Tel.: 33-(0)4-86-97-74-07 Academic Editor: Eishi Noguchi Received: 2 November 2016; Accepted: 23 January 2017; Published: 31 January 2017 Abstract: Telomeres are complex nucleoprotein structures that protect the extremities of linear chromosomes. Telomere replication is a major challenge because many obstacles to the progression of the replication fork are concentrated at the ends of the chromosomes. This is known as the telomere replication problem. In this article, different and new aspects of telomere replication, that can threaten the integrity of telomeres, will be reviewed. In particular, we will focus on the functions of shelterin and the replisome for the preservation of telomere integrity. Keywords: telomere; telomere replication; G-quadruplex; T-loop; TERRA 1. Introduction The linearization of chromosomes in eukaryotes allows the shuffling of alleles between homologous chromosomes during meiosis [1,2]. The extremities of linear chromosomes, named telomeres, are a consequence of this evolutionary change in eukaryotes, and could be considered as the “Achilles heel” of a chromosome. Mammalian telomeres contain several kilobases (5–15 kb) of tandemly-repeated sequences (50-TTAGGG-30) that terminate with 30–400 nucleotides of single-strand DNA on the G-rich strand, called the 30 overhang. Mammalian telomeric DNA can fold back into a T-loop structure, in which the 30 overhang invades the duplex DNA of repeated sequences. TTAGGG sequences are specifically recognized by several telomeric proteins, that together form the shelterin complex [3] (Figure1). The telomeric repeat binding factor 1 and 2 (TRF1 and TRF2) bind to double-strand telomeric tracks, while the protection of telomeres 1 protein (POT1) binds to the 30 overhang. TRF1 and TRF2 recruit the other components of shelterin: TRF2 and TRF1-interacting nuclear protein 2 (TIN2), the human ortholog of the yeast repressor/activator protein 1 (RAP1), and TPP1, also called TINT1, PTOP and PIP1. One function of shelterin is to protect the physical chromosome ends by inhibiting the DNA damage response pathways, including activation of the checkpoint kinases ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-Related (ATR), as well as classical and alternative non-homologous end joining (NHEJ) [4]. Dysfunctional shelterin, which can be caused by the downregulation of TRF2, may eventually lead to telomere fusions, p53-dependent cell cycle arrest in G1, and senescence [3]. In the absence of p53 function, telomere fusions trigger cell death during mitosis [5]. Thus, shelterin is essential for the stability of the linear genomes. At each cell division, the telomeres shorten because of the incomplete replication of the linear DNA molecules by the conventional DNA polymerases. This is called the end replication problem [6]. This is specifically due to the resection and fill-in reaction during the synthesis of the telomere leading-strand [7,8]. To circumvent this irremediable telomeric loss, shelterin also functions to recruit a reverse transcriptase called telomerase, that is able to elongate the 30 overhang by the addition of telomeric repeats. The telomerase is a ribonucleoprotein minimally comprised of the catalytic subunit (TERT, telomerase reverse transcriptase) and its intrinsic RNA (TERC, telomerase RNA component). The TERT subunit is recruited to telomeres through its association with TPP1 during the S phase of the Genes 2017, 8, 55; doi:10.3390/genes8020055 www.mdpi.com/journal/genes Genes 2017, 8, 55 2 of 15 RNA component). The TERT subunit is recruited to telomeres through its association with TPP1 during the S phase of the cell cycle [9,10], and is inhibited by the CTC1–STN1–TEN1 complex (CST) Genes 2017, 8, 55 2 of 16 that acts as a terminator of telomerase activity [11]. In addition, the CST complex stimulates the DNA polymerase α/primase for the synthesis of the complementary strand [12]. In the absence of telomerasecell cycle [9 activity,,10], and telomeres is inhibited undergo by the CTC1–STN1–TEN1gradual shortening, complexleading to (CST) the thatinhibition acts as of a proliferation terminator of viatelomerase either replicative activity [11 ].senescence In addition, [13], the or CST more complex rarely, stimulates by apoptosis the DNA (depending polymerase onα /primasethe cellular for context).the synthesis One ofof thethe complementaryhallmarks of cancer strand cells [12 ].is Intheir the ability absence to of proliferate telomerase indefinitely. activity, telomeres Indeed, undergo cancer cellsgradual counteract shortening, the leadingshortening to theof inhibitiontelomeres ofeither proliferation by re-activating via either telomerase, replicative senescenceor by using [13 a], homologousor more rarely, recombination by apoptosis (dependingtelomere-copying on the cellularmechanism, context). known One ofas the alternative hallmarks lengthening of cancer cells of is telomerestheir ability (ALT). to proliferate indefinitely. Indeed, cancer cells counteract the shortening of telomeres either by re-activatingIn mammalian telomerase, cells, the ormajority by using of atelomeres homologous are replicated recombination throughout telomere-copying the S phase mechanism, [14,15]. In contrast,known as in alternative budding and lengthening fission yeasts, of telomeres telomeric (ALT). DNA replication occurs at the end of the S phase [16,17].In Short mammalian telomeres, cells, however, the majority replicate oftelomeres earlier [18,19], are replicated and this is throughout facilitated by the Tel1 S phase in budding [14,15]. yeastIn contrast, [20]. Remarkably, in budding when and fission the global yeasts, replication telomeric program DNA replication is perturbed, occurs telomeres at the end are of also the replicatedS phase [16 earlier,,17]. Short modifying telomeres, the however, telomere replicate length earlierequilibrium [18,19 ],[21,22]. and this This is facilitatedunderscores by Tel1the importancein budding of yeast the [accurate20]. Remarkably, timing of when telomeric the global sequence replication replication, program which is perturbed,is a prerequisite telomeres for telomereare also replicatedhomeostasis earlier, and telomerase modifying control the telomere in yeast. length Moreover, equilibrium it becomes [21,22 clear]. This that underscores any obstacles the thatimportance impede ofreplication the accurate fork timing progression of telomeric will generate sequence a replication, stress which which alters is atelomere prerequisite length for homeostasis.telomere homeostasis This defines and the telomerase telomere controlreplication in yeast. problem Moreover, [23]. Out it becomesof the entire clear genome, that any telomeres obstacles arethat one impede of the replication most difficult fork progression regions to willreplicate generate because a stress they which encompass alters telomere multiple length difficulties homeostasis. for replication.This defines In the this telomere essay, replicationwe will review problem different [23]. Out and of thenew entire aspects genome, of telomere telomeres replication are one ofthat the threatenmost difficult the integrity regions of to telomeres, replicate because examining they how encompass the replication multiple machinery difficulties and for shelterin replication. deal In with this thisessay, challenge. we will review different and new aspects of telomere replication that threaten the integrity of telomeres, examining how the replication machinery and shelterin deal with this challenge. FigureFigure 1. The vertebratevertebrate shelterinshelterin complex. complex. Telomeric Telomeri repeatc repeat binding binding factors factors 1 and 1 and 2 (TRF1 2 (TRF1 and TRF2) and TRF2)bind tobind double-stranded to double-stranded telomeric telomeric DNA and recruitDNA otherand recruit components other of components shelterin: TRF1-interacting of shelterin: TRF1-interactingnuclear protein 2nuclear (TIN2), protein the human 2 (TIN2), ortholog the ofhuman the yeast ortholog repressor/activator of the yeast repressor/activator protein 1 (RAP1), proteinand tripeptidyl 1 (RAP1), peptidase and tripeptidyl 1 (TPP1). peptidase Protection 1 (TPP1) of telomeres. Protection 1 (POT1) of telomeres protein 1 binds(POT1) to protein the telomeric binds tosingle-stranded the telomeric single-stranded DNA. Shelterin DNA. promotes Shelterin the fold-back promotes of the telomeric fold-back DNA of intotelomeric a T-loop DNA structure into a T-loopthrough structure formation through of a D-loop. formation of a D-loop. 2.2. Telomeres, Telomeres, a a Source Source of of Replication Replication Stress Stress TelomereTelomere replicationreplication mostlymostly proceeds proceeds unidirectionally, unidirectionally, from from a centromere-proximal a centromere-proximal origin. origin. DNA DNAtwo-dimensional two-dimensional gel electrophoresis gel electrophoresis analysis (2D-gel)analysis in (2D-gel) yeast has in demonstrated yeast has thatdemonstrated replication forksthat replicationnaturally slow forks and naturally eventually slow stall, and aseventually they approach stall, as telomeric they approach chromatin telo [meric23–25 ].chromatin If stalling [23–25]. persists,
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