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Telomere-Regulating Genes and the Telomere Interactome in Familial Cancers Carla Daniela Robles-Espinoza1, Martin Del Castillo Velasco-Herrera1, Nicholas K

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Telomere-Regulating Genes and the Telomere Interactome in Familial Cancers Carla Daniela Robles-Espinoza1, Martin Del Castillo Velasco-Herrera1, Nicholas K Published OnlineFirst September 22, 2014; DOI: 10.1158/1541-7786.MCR-14-0305 Review Molecular Cancer Research Telomere-Regulating Genes and the Telomere Interactome in Familial Cancers Carla Daniela Robles-Espinoza1, Martin del Castillo Velasco-Herrera1, Nicholas K. Hayward2, and David J. Adams1 Abstract Telomeres are repetitive sequence structures at the ends of linear mutations in telomere-regulating proteins and their interacting chromosomes that consist of double-stranded DNA repeats fol- partners have been found to underlie a variety of diseases and lowed by a short single-stranded DNA protrusion. Telomeres need cancer-predisposition syndromes. These syndromes can be char- to be replicated in each cell cycle and protected from DNA-proces- acterized by progressively shortening telomeres, in which carriers sing enzymes, tasks that cells execute using specialized protein can present with organ failure due to stem cell senescence among complexes such as telomerase (that includes TERT), which aids in other characteristics, or can also present with long or unprotected telomere maintenance and replication, and the shelterin complex, telomeres, providing an alternative route for cancer formation. This which protects chromosome ends. These complexes are also able to review summarizes the critical roles that telomere-regulating pro- interact with a variety of other proteins, referred to as the telomere teins play in cell-cycle control and cell fate and explores the current interactome, to fulfill their biological functions and control sig- knowledge on different cancer-predisposing conditions that have naling cascades originating from telomeres. Given their essential been linked to germline defects in these proteins and their inter- role in genomic maintenance and cell-cycle control, germline acting partners. Mol Cancer Res; 13(2); 211–22. Ó2014 AACR. Introduction called telomerase that is able to add TTAGGG repeats to the ends of chromosomes (10). In most somatic cells, telomerase is under Telomeres are specialized structures at the ends of linear chro- stringent control and expressed only transiently and at low levels, mosomes that consist of arrays of repeated nucleotide sequences. the exception being cells that are undergoing rapid proliferation Telomeres play an essential role in regulating genomic stability by such as bone marrow precursors cells, as well as embryonic or adult allowing the cell to distinguish between chromosome ends and stem cells (11–13). However, the level of telomerase expression in double-strand DNA breaks, a function that is controlled by somatic tissues is insufficient to sustain indefinite cell proliferation, adopting characteristic chromosomic structures and by complexes and so telomeres progressively erode with each cell division, of telomere-binding proteins. Protein complexes also control ultimately resulting in cell senescence or death (reviewed in ref. 14). telomere length, access of the DNA repair machinery, and telo- In addition to carefully regulating the length of telomeres, cells mere end-protection, which is also known as "capping" (1–3). In also need to distinguish telomere ends from DNA breaks that need humans and other vertebrates, telomeres comprise 9 to 15 kilo- to be repaired. Chromosome ends can adopt alternative structures bases of double-stranded TTAGGG repeats, followed by a 50- to that probably aid in this function. For example, the G-strand 300-nucleotide protrusion of G-rich short single-stranded DNA overhang is able to form G-quadruplexes, which are stacks of (ssDNA), known as the G-strand overhang (3–5). planar arrays of four G's hydrogen bonded by Hoogsteen base Tight regulation of telomere length is essential for normal cell pairs (15, 16). This single-stranded overhang is also able to invade function. In the absence of telomere length maintenance mechan- the double-stranded region of the telomere, forming what are isms, the ends of chromosomes are shortened with each round of referred to as D- and T-loops and shielding the ssDNA from cell division due to the inability of the replication machinery to nucleases and DNA-processing enzymes (2, 17, 18; Fig. 1A). The fully synthesize the 50 end of the lagging strand (6), as well as the shelterin complex, a large macromolecular structure composed of need to enzymatically generate the G-strand overhang (7–9). To six proteins, also contributes to this function by binding to counteract these effects, cells use a specialized enzyme complex telomeres and inhibiting DNA repair, while also contributing to telomere length control by regulating access of telomerase to 1Experimental Cancer Genetics,Wellcome Trust Sanger Institute, Hinx- telomeres (2, 19; Fig. 1A). Alterations to telomere structure, or 2 ton, United Kingdom. Oncogenomics Laboratory, QIMR Berghofer the loss of shelterin, result in defects in sister chromatid exchange, Medical Research Institute, Herston, Brisbane, Queensland, Australia. telomere fusions, polyploidization, telomere length dysregula- Note: Supplementary data for this article are available at Molecular Cancer tion, and other chromosomal abnormalities (2, 5, 20). The Research Online (http://mcr.aacrjournals.org/). structures of telomerase and shelterin, as well as their roles in Corresponding Author: Carla Daniela Robles-Espinoza, Wellcome Trust Sanger telomere protection and length regulation, are discussed in more Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, detail in the next section. UK. Phone: 44-1223-834244; Fax: 44-1223-494919; E-mail: [email protected] Telomerase and shelterin, with key roles in the regulation of doi: 10.1158/1541-7786.MCR-14-0305 telomere length and end-protection, have altered expression or Ó2014 American Association for Cancer Research. are affected by somatic mutations in cancers (21–23), which www.aacrjournals.org 211 Downloaded from mcr.aacrjournals.org on September 27, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst September 22, 2014; DOI: 10.1158/1541-7786.MCR-14-0305 Robles-Espinoza et al. A ′ ′ ′ ′ B ′ ′ ′ ′ Figure 1. Telomere-interacting proteins and their roles. A, the shelterin complex, composed of six proteins (left), and several of its associated proteins are depicted with the biological functions they play in the cell (right). For simplicity, TERF1 and TERF2 homodimers are drawn as single boxes. The alternative T- and D-loop telomere structures are shown. Tnk, Tankyrase; Ub, ubiquitination; P, phosphorylation; ADPr, ADP ribosylation. B, the members of the telomerase complex are shown bound to the G-strand overhang with a simplified structure for TERC, which provides the template for repeat addition. confers upon malignant cells the ability to bypass senescence The template for DNA synthesis is provided by TERC, a 451- while promoting genomic instability. Many cancers display nucleotide–long RNA subunit that can bind accessory proteins as increased telomerase activity or have activated the alternative well as TERT to ensure its own stability and telomerase biogenesis lengthening of telomeres (ALT) pathway leading to sustained or localization (15, 30). The highly conserved TERT subunit telomere maintenance (reviewed in ref. 24). Further, ectopic provides the catalytic site for the addition of telomeric repeats to expression of telomerase has been shown to elicit replicative the end of chromosomes, and its amino acid sequence contains immortality in certain cell types, a hallmark of cancer (25, 26). domains for binding TERC and for forming a closed ring-like It has also been suggested that shelterin complex mutations might structure that can bind the DNA–RNA duplex (15, 31). Dyskerin facilitate the acquisition of somatic aberrations, therefore driving is an essential protein that associates with TERC and is required for cancer progression through accelerated tumor evolution (23, 27). its correct processing, as well as for telomerase activity and stability, Here, we discuss what is known about cancer-predisposition and is found in a complex with both TERT and TERC when the syndromes driven by germline variants in telomere-regulating catalytic enzyme is purified from cell lines (32, 33). Dyskerin can proteins. also bind the accessory proteins NOP10, NHP2, and GAR1 to form a subcomplex that is necessary for TERC accumulation in vivo Proteins Involved in Telomere Maintenance (reviewed in ref. 12; Fig. 1B). If proteins such as TCAB1 or EST1A are defective or abnormally expressed, then telomerase function is In this section, we briefly discuss the proteins and complexes impaired due to mislocalization of TERC to the nucleoli or by involved in telomere maintenance. telomere structural abnormalities (29, 34, 35). In normal somatic cells, telomerase is assembled in Cajal Telomerase bodies, which are specialized RNA-processing suborganelles in This protein complex is formed by two core subunits: the the cell nucleus (36). It is then shipped to telomeres by TCAB1 and catalytic telomerase reverse transcriptase (encoded by TERT) and modified into an active conformation by Reptin and Pontin, by the telomerase RNA component (TERC, also known as TR; which point it is able to start adding nucleotides to the ends of refs. 17, 28; Fig. 1B). Several additional accessory factors are telomeres (5, 37, 38). Telomerase is active during the S-phase of necessary for telomerase assembly and activation, such as the the cell cycle, and it is thought that it targets telomeres for auxiliary protein dyskerin (encoded by DKC1), the localization
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