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Role of TERRA in the Regulation of Telomere Length Caiqin Wang, Li Zhao, Shiming Lu 

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Role of TERRA in the Regulation of Telomere Length Caiqin Wang, Li Zhao, Shiming Lu  Int. J. Biol. Sci. 2015, Vol. 11 316 Ivyspring International Publisher International Journal of Biological Sciences 2015; 11(3): 316-323. doi: 10.7150/ijbs.10528 Review Role of TERRA in the Regulation of Telomere Length Caiqin Wang, Li Zhao, Shiming Lu Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, China, Women’s Hospital, School of Medicine, Zhejiang University, Xueshi Road 1#, Hangzhou 310006, China Corresponding author: Shiming Lu, Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, China, Women’s Hospital, School of Medicine, Zhejiang University, Xueshi Road 1#, Hangzhou 310006, China; E-mail: [email protected] © 2015 Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions. Received: 2014.09.11; Accepted: 2014.12.25; Published: 2015.02.05 Abstract Telomere dysfunction is closely associated with human diseases such as cancer and ageing. Inap- propriate changes in telomere length and/or structure result in telomere dysfunction. Telomeres have been considered to be transcriptionally silent, but it was recently demonstrated that mammalian telomeres are transcribed into telomeric repeat-containing RNA (TERRA). TERRA, a long non-coding RNA, participates in the regulation of telomere length, telomerase activity and heterochromatinization. The correct regulation of telomere length may be crucial to telomeric homeostasis and functions. Here, we summarize recent advances in our understanding of the crucial role of TERRA in the maintenance of telomere length, with focus on the variety of mechanisms by which TERRA is involved in the regulation of telomere length. This review aims to enable further understanding of how TERRA-targeted drugs can target telomere-related diseases. Key words: TERRA, telomere length, telomerase, HDR, ALT, protection of chromosome end Introduction Telomeres were identified in the 1930s and are promoted by TRF2. T–loops generated from the 3′ nucleoprotein structures that protect the ends of G-overhang provide a protective cap that can protect chromosomes from being recognized and processed against DNA damage induced by the DNA damage as DNA double-strand breaks (DSBs) and from deg- response (DDR) machinery [7]. radation [1]. Human telomeres extend from 9–15 Kb, Telomeres shorten following each cell division but can be as long as 100 Kb in rodents [1, 2]. Human via a phenomenon termed the end-replication prob- and mouse telomeres are composed of long tracts of lem [8] and exonuclease-mediated processing [9]. double-stranded G rich TTAGGG repeats and a telo- When telomeres become shortened below a critical mere-specific protein complex, shelterin. The shelterin length, they can lose their protective function. To date, complex consists of six protein subunits: telomeric two mechanisms have been identified that prevent repeat binding factor-1 (TRF1), TRF2, re- telomere shortening: firstly, telomere elongation by pressor/activator protein-1 (RAP1), TRF1-interacting the ribonucleoprotein enzyme telomerase, telomerase protein-2 (TIN2), TINT1/PIP1/PTOP 1 (TPP1) and adds telomeric repeats to chromosome ends and has a protection of telomeres-1 (POT1), and regulates the strong preference for short telomeres [10], and sec- maintenance of telomere length and protects natural ondly, the telomere maintenance mechanism (TMM), chromosome ends from being recognized as damaged which depends on homology-directed repair (HDR) DNA [1, 3-5]. Single-stranded repeat structures cre- to elongate telomeres and is also termed alternative ated by 5′ to 3′ exonucleases and termed G-overhangs lengthening of telomeres (ALT). ALT occurs in ap- protrude from the 3′ end of telomeres [6]. The inva- proximately 10–15% of human cancer cells [11-13], in sion of the 3′ telomeric overhang into the duplex te- which telomere elongation occurs in ALT-related lomeric array forms a T-loop, and this process is PML bodies (APBs), a specific class of promyelocytic http://www.ijbs.com Int. J. Biol. Sci. 2015, Vol. 11 317 leukemia (PML) nuclear bodies that includes PML human TRF1; silencing of TRF1 using small interfer- protein, telomeric DNA, telomere-specific proteins, ing RNA (siRNA) decreased the expression of TERRA and recombination and repair proteins [14]. Telomeric by two-fold in murine C2C12 cells [27]. In yeast, the material is recruited to PML bodies to initiate recom- 5′-3′ exonuclease, Rat1, negatively regulates the levels bination. In ALT cells, the presence of APBs plays a of TERRA via a mechanism that is mediated in part by positive role in telomere maintenance; furthermore, the Saccharomyces cerevisiae repressor-activator protein PML bodies can modify telomere-associated chroma- 1, Rap1, and its interacting proteins, Rif1 and Rif2 [18, tin and improve the stability of telomeres [15]. The 28]. TRF4, an alternative poly(A) polymerase that is role of APBs in telomere length maintenance remains often associated with exosomal-mediated degrada- unclear, although it has been suggested to be the site tion, also plays a minor role in the degradation of of telomere recombination, so we will not further TERRA, but only in Rat1-deficient cells. On the other discuss this problem here. hand, overexpression of RNAse H, which degrades For many years, telomeres have been considered RNA in RNA–DNA hybrid molecules, reduced the to be transcriptionally silent; in 2007, it was demon- expression of TERRA in budding yeast. strated that mammalian telomeres are indeed tran- TERRA participates in multiple regulatory func- scribed into telomeric repeat–containing RNA tions, such as telomerase activity [29-32], hetero- (TERRA) [16]. In a similar manner to long noncoding chromatinization of telomeres [33] and development, RNAs (lncRNAs), TERRA participates in the fine reg- such as cellular differentiation [27, 34-36]. TERRA has ulation of cell biology, which opens a new field in the been confirmed to associate with telomeres via teth- understanding of telomeric functions and related ering in a DNA–RNA hybrid formation [18, 37] or via diseases. TERRA molecules localize to telomeres and interaction of RNA-binding proteins with telomeres regulate telomerase activity, telomere length and as- [38]. For example, members of the heterogeneous nu- sociated heterochromatinization. Changes in the ex- clear ribonucleoprotein (hnRNP) family can assist in pression level of TERRA are associated with altered the binding of TERRA to telomeres and influence the telomeric length and promote genome instability and levels of TERRA by regulating the stability of the cellular senescence. In this review, we discuss the transcripts [39]. Recently, systematic, comprehensive, present knowledge of TERRA biogenesis, structure quantitative proteomic analysis of proteins that in- and functional regulation, and particularly focuses on teract with non-coding repetitive RNA led to the the various mechanisms that regulate telomere length. identification of novel interactors that play a role in TERRA homeostasis and its association with telo- Biogenesis, structure and functional reg- meres. This work indicated that the telomere binding ulation of TERRA proteins, TRF1, and the component of the Nua4 his- Telomeric repeat-containing RNA (TERRA) is tone acetyltransferase complex, MORF4L2, may be transcribed from several subtelomeric loci located required for the transcription or transcriptional sta- close to chromosome ends, is composed of varying bility of TERRA and telomere binding [40]. Further sizes of UUAGGG repeat sequences and ranges in size discovery of additional TERRA-associated proteins from 100 bp to 9 Kb in mammals [16]. TERRA is ex- may help to more precisely characterize the function pressed in most mammalian tissues. Approximately of TERRA. 7% of human TERRA molecules are polyadenylated TERRA promotes telomere shortening [17] whereas most or all yeast TERRA molecules carry a poly(A) tail [18], and all human and most yeast For several years, research interest in TERRA TERRA 5′ ends contain a 7-methylguanosine (m7G) mainly focused on yeast cells, human tumor cells and cap structure [19]; these features increase the stability stem cells. In Saccharomyces cerevisiae, Rat1p, a yeast 5′ of TERRA molecules. Furthermore, TERRA forms to 3′ RNA exonuclease, degrades TERRA and pro- stable G-quadruplexes in vitro and in vivo [20-26], and motes telomere elongation; when Rat1p is mutated, there is direct evidence that TERRA binds to the te- TERRA accumulates and forms a DNA/RNA hybrid lomeric protein TRF2 by forming an intramolecular that inhibits telomerase activity at telomeres and re- G-quadruplex structure [25]; additional characteriza- sults in telomere shortening [18]. Furthermore, tion of this structure may help to further understand TERRA interacts with the Exo1-inhibiting Ku70/80 the molecular interactions between nucleic acids and dimer that promotes Exo1-dependent resection at proteins at chromosome ends and design telo- chromosome ends during telomere shortening [41]. In mere-targeting loci for therapy in the future. TERRA the absence of a telomere maintenance mechanism, it is mainly transcribed by RNA polymerase II has been reported that increased telomere transcrip- (RNAPII); this process has been reported to be regu- tion results in telomere shorting as a result of DNA lated by telomeric heterochromatin and is promoted replication-dependent loss of telomere
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