RNA BIOLOGY 2016, VOL. 13, NO. 8, 681–682 http://dx.doi.org/10.1080/15476286.2016.1211223
GUEST EDITORIAL
Special focus on telomeres and telomerase Pascal Chartrand Universite de Montreal, Montreal, Quebec, Canada ARTICLE HISTORY Received 5 July 2016; Accepted 6 July 2016
Telomeres are repetitive DNA elements that cap the ends of linear chromosomes, maintain their integrity and inhibit fusion or recombination between chromosomes. Telomeres are not naked DNA but are protected by a multiprotein complex called shelterin which, in human cells, is composed of the telomeric double-strand DNA binding proteins TRF1 and TRF2, the single-strand telomeric binding protein POT1, and other interacting factors such as TPP1, RAP1 and TIN2. In most eukaryotes, the specialized ribonucleoprotein (RNP) complex telomerase is responsible for maintaining telomeres length. This complex is minimally composed of a catalytic subunit called TERT, which possesses a reverse transcriptase activity, and a non-coding RNA called TR (or TERC), which contains the template for telomeric DNA synthesis and acts as a scaffold for the assembly of the telomerase holoenzyme. While in somatic cells telomerase activity is limited, reactivation of telomerase is a key event leading to cellular immortalization and unlimited proliferation of cancer cells. For this reason, much emphasis has been put in the study of the role of telomerase and telomeres in genomic integrity and tumorigenesis. Despite our growing understanding of telomeres biology, several questions in the field remain unanswered, new actors involved in telomere maintenance are still being discovered and novel biological functions of telomerase are emerging. The main purpose of this Special Focus on Telomeres and Telomerase is to review some of these questions and discuss recent findings in telomere biology and on telomerase, focusing on some of the RNA molecules associated with telomere biology. Telomerase is the solution to the end-replication problem in most eukaryotes. Although telomerase function is highly conserved during evolution, telomerase RNAs are highly diverse in term of sequence, length or structure among various species. Still, specific functional domains have been identified in telomerase RNAs, some of them being highly conserved. In their Review, Podlevsky and Chen provide an evolutionary perspective on telomerase RNA structure and function.1 The authors particularly explore the diversity within the functional domains found in telomerase RNAs, which reflects in part the various biogenesis pathways through which these RNAs are processed among eukaryotes. Even if telomerase RNA has been extensively studied in various organisms, the specific function of some of its highly conserved domains remains unclear. One example is the CR4/CR5 domain or STE (Stem terminus element), which is conserved CONTACT Pascal Chartrand © 2016 Taylor & Francis Group, LLC
[email protected]
between vertebrates, fission yeasts and filamentous fungi. This domain interacts with TERT and is essential for telomerase activity, but its specific function is still unknown. In their Point-of-View, Webb and Zakian discuss about the function of the STE domain, and propose a role for this domain in the fidelity of telomere sequence addition by telomerase.2 Novel players in telomere biology have emerged in the past few years. Among them are several non-coding RNAs transcribed from telomeric or subtelomeric regions. One of these non-coding RNAs, the telomeric repeat-containing RNA TERRA, is transcribed from subtelomeric promoters toward the telomeric repeats and has been detected in several organisms. Several possible functions for TERRA have been suggested since its discovery: as a regulator of telomerase, in the regulation of POT1 binding to telomeres during the cell cycle or in the recruitment of chromatin modification factors at telomeres. In a Point-of-View recently published in RNA Biology, Arora and Azzalin review the putative roles of TERRA in telomere biology, focusing on the implication of TERRA in the alternative maintenance of telomeres (ALT), which occurs independently of telomerase and depends on recombination between telomeres.3 Novel functions for TERRA are still emerging and, surprisingly, not all of them are in telomere biology. For instance, in another Point-of-view in this issue, Wang and Lieberman discuss an unexpected role for TERRA in the inflammatory response, in which a cell-free form of TERRA enriched in extracellular exosomes can stimulate inflammatory cytokines in immune responsive cells.4 Other non-coding RNAs beside TERRA participate in telomere biology. In a short research article published in this Special Issue, Fuhrmann and colleagues reveal that telomeric repeat-containing dsRNA can act as template for de novo telomere addition at the ends of nanochromosomes during the differentiation of the macronucleus of ciliates.5 The importance of telomere maintenance and telomerase reactivation in cellular immortalization and transformation is well established and has been extensively studied over several decades. These observations led researchers to consider telomerase as a key cancer-specific therapeutic target. Beside telomerase, telomeres and the shelterin complex themselves are now considered putative therapeutic targets since rapidly dividing cancer cells are particularly sensitive to telomere deprotection. A Pointof-View recently published in RNA Biology by Rousseau and Autexier provides an overview of our current knowledge on
682
P. CHARTRAND
telomerase and telomeres in cancer, focusing on the therapeutic and diagnostic potentials of telomere biology to fight cancer.6 Telomerase expression is not a feature unique to cancer cells. Germ cells and stem cells renewal also depends on telomere repeat addition by telomerase. However, recent studies suggest novel functions for TERT in stem cells beside telomeres maintenance, such as the regulation of the Wnt/b-catenin pathway or mitochondrial function. These non-canonical functions of TERT do not require telomerase RNA and occur independently of telomerase catalytic activity. In their Review article, Dean Betts and colleagues describe the roles of TERT in the induction and maintenance of pluripotent stem cells,7 with a special focus on the non-canonical functions of TERT and on alternative splicing variants of TERT, which are particularly abundant in stem cells. The contribution of telomerase and telomeres in the etiology of genetic diseases has been for a long time overshadowed by their role in cellular immortalization and tumorigenesis. Telomere biology disorders (TBDs) or telomeropathies are now coming upfront in telomere research. Several of these diseases, such as dyskeratosis congenita, aplastic anemia, idiopathic pulmonary fibrosis, Coats’ plus, Hoyeraal Hreidarsson and Revesz syndromes, are linked to mutations in telomerase subunits and/ or components of the shelterin complex. The recent discoveries in the genetics of telomere biology disorders is covered by a Review of Alison Bertuch, which particularly highlights the role of mutations in genes that do not encode for known members of telomerase or the shelterin complex, like mutations in PARN, which encodes a poly(A)-specific 30 exoribonuclease.8 In light of recent studies that have shown that PARN is important for 30 end processing and accumulation of hTR, this raises the possibility that other genes involved in telomerase biogenesis may be mutated in patients with TBDs. The collection of articles in this special issue of RNA Biology presents some of the current knowledge on telo-
meres and telomerase, and how it impacts our understanding of cancer, stem cells and telomeropathies. Altogether, these articles show that there is still much to learn about the various facets of telomerase biology, and on the role of novel non-coding RNAs such as TERRA in the maintenance of telomeres.
Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.
References 1. Podlevsky JD, Chen JJ-L. Evolutionary perspectives of telomerase RNA structure and function. RNA Biol 2016; 13:720-32; PMID:27359343; http://dx.doi.org/10.1080/15476286.2016.1205768 2. Webb CJ, Zakian VA. Telomerase RNA is more than a DNA template. RNA Biol 2016; 13:683-89; PMID:27245259; http://dx.doi. org/10.1080/15476286.2016.1191725 3. Arora R, Azzalin CM. Telomere elongation chooses TERRA ALTernatives. RNA Biol 2015; 12:938-41; PMID:26158306; http://dx.doi.org/ 10.1080/15476286.2015.1065374 4. Wang Z, Lieberman PM. The crosstalk of telomere dysfunction and inflammation through cell-free TERRA containing exosomes. RNA Biol 2016; 13:690-95; PMID:27351774; http://dx.doi.org/ 10.1080/15476286.2016.1203503 5. Fuhrmann G, J€ onsson F, Weil PP, Postberg J, Lipps HJ. RNA-template dependent de novo telomere addition. RNA Biol 2016; 13:733-39; PMID:26786510; http://dx.doi.org/10.1080/15476286.2015.1134414 6. Rousseau P, Autexier C. Telomere biology: Rationale for diagnostics and therapeutics in cancer. RNA Biol 2015; 12:1078-82; PMID:26291128; http://dx.doi.org/10.1080/15476286.2015.1081329 7. Teichroeb JH, Kim J, Betts DH. The role of telomeres and telomerase reverse transcriptase isoforms in pluripotency induction and maintenance. RNA Biol 2016; 13:707-19; PMID:26786236; http://dx.doi.org/ 10.1080/15476286.2015.1134413 8. Bertuch AA. The molecular genetics of the telomere biology disorders. RNA Biol 2016; 13:696-706; PMID:26400640; http://dx.doi.org/ 10.1080/15476286.2015.1094596
GUEST EDITORIAL
Special focus on telomeres and telomerase Pascal Chartrand Universite de Montreal, Montreal, Quebec, Canada ARTICLE HISTORY Received 5 July 2016; Accepted 6 July 2016
Telomeres are repetitive DNA elements that cap the ends of linear chromosomes, maintain their integrity and inhibit fusion or recombination between chromosomes. Telomeres are not naked DNA but are protected by a multiprotein complex called shelterin which, in human cells, is composed of the telomeric double-strand DNA binding proteins TRF1 and TRF2, the single-strand telomeric binding protein POT1, and other interacting factors such as TPP1, RAP1 and TIN2. In most eukaryotes, the specialized ribonucleoprotein (RNP) complex telomerase is responsible for maintaining telomeres length. This complex is minimally composed of a catalytic subunit called TERT, which possesses a reverse transcriptase activity, and a non-coding RNA called TR (or TERC), which contains the template for telomeric DNA synthesis and acts as a scaffold for the assembly of the telomerase holoenzyme. While in somatic cells telomerase activity is limited, reactivation of telomerase is a key event leading to cellular immortalization and unlimited proliferation of cancer cells. For this reason, much emphasis has been put in the study of the role of telomerase and telomeres in genomic integrity and tumorigenesis. Despite our growing understanding of telomeres biology, several questions in the field remain unanswered, new actors involved in telomere maintenance are still being discovered and novel biological functions of telomerase are emerging. The main purpose of this Special Focus on Telomeres and Telomerase is to review some of these questions and discuss recent findings in telomere biology and on telomerase, focusing on some of the RNA molecules associated with telomere biology. Telomerase is the solution to the end-replication problem in most eukaryotes. Although telomerase function is highly conserved during evolution, telomerase RNAs are highly diverse in term of sequence, length or structure among various species. Still, specific functional domains have been identified in telomerase RNAs, some of them being highly conserved. In their Review, Podlevsky and Chen provide an evolutionary perspective on telomerase RNA structure and function.1 The authors particularly explore the diversity within the functional domains found in telomerase RNAs, which reflects in part the various biogenesis pathways through which these RNAs are processed among eukaryotes. Even if telomerase RNA has been extensively studied in various organisms, the specific function of some of its highly conserved domains remains unclear. One example is the CR4/CR5 domain or STE (Stem terminus element), which is conserved CONTACT Pascal Chartrand © 2016 Taylor & Francis Group, LLC
[email protected]
between vertebrates, fission yeasts and filamentous fungi. This domain interacts with TERT and is essential for telomerase activity, but its specific function is still unknown. In their Point-of-View, Webb and Zakian discuss about the function of the STE domain, and propose a role for this domain in the fidelity of telomere sequence addition by telomerase.2 Novel players in telomere biology have emerged in the past few years. Among them are several non-coding RNAs transcribed from telomeric or subtelomeric regions. One of these non-coding RNAs, the telomeric repeat-containing RNA TERRA, is transcribed from subtelomeric promoters toward the telomeric repeats and has been detected in several organisms. Several possible functions for TERRA have been suggested since its discovery: as a regulator of telomerase, in the regulation of POT1 binding to telomeres during the cell cycle or in the recruitment of chromatin modification factors at telomeres. In a Point-of-View recently published in RNA Biology, Arora and Azzalin review the putative roles of TERRA in telomere biology, focusing on the implication of TERRA in the alternative maintenance of telomeres (ALT), which occurs independently of telomerase and depends on recombination between telomeres.3 Novel functions for TERRA are still emerging and, surprisingly, not all of them are in telomere biology. For instance, in another Point-of-view in this issue, Wang and Lieberman discuss an unexpected role for TERRA in the inflammatory response, in which a cell-free form of TERRA enriched in extracellular exosomes can stimulate inflammatory cytokines in immune responsive cells.4 Other non-coding RNAs beside TERRA participate in telomere biology. In a short research article published in this Special Issue, Fuhrmann and colleagues reveal that telomeric repeat-containing dsRNA can act as template for de novo telomere addition at the ends of nanochromosomes during the differentiation of the macronucleus of ciliates.5 The importance of telomere maintenance and telomerase reactivation in cellular immortalization and transformation is well established and has been extensively studied over several decades. These observations led researchers to consider telomerase as a key cancer-specific therapeutic target. Beside telomerase, telomeres and the shelterin complex themselves are now considered putative therapeutic targets since rapidly dividing cancer cells are particularly sensitive to telomere deprotection. A Pointof-View recently published in RNA Biology by Rousseau and Autexier provides an overview of our current knowledge on
682
P. CHARTRAND
telomerase and telomeres in cancer, focusing on the therapeutic and diagnostic potentials of telomere biology to fight cancer.6 Telomerase expression is not a feature unique to cancer cells. Germ cells and stem cells renewal also depends on telomere repeat addition by telomerase. However, recent studies suggest novel functions for TERT in stem cells beside telomeres maintenance, such as the regulation of the Wnt/b-catenin pathway or mitochondrial function. These non-canonical functions of TERT do not require telomerase RNA and occur independently of telomerase catalytic activity. In their Review article, Dean Betts and colleagues describe the roles of TERT in the induction and maintenance of pluripotent stem cells,7 with a special focus on the non-canonical functions of TERT and on alternative splicing variants of TERT, which are particularly abundant in stem cells. The contribution of telomerase and telomeres in the etiology of genetic diseases has been for a long time overshadowed by their role in cellular immortalization and tumorigenesis. Telomere biology disorders (TBDs) or telomeropathies are now coming upfront in telomere research. Several of these diseases, such as dyskeratosis congenita, aplastic anemia, idiopathic pulmonary fibrosis, Coats’ plus, Hoyeraal Hreidarsson and Revesz syndromes, are linked to mutations in telomerase subunits and/ or components of the shelterin complex. The recent discoveries in the genetics of telomere biology disorders is covered by a Review of Alison Bertuch, which particularly highlights the role of mutations in genes that do not encode for known members of telomerase or the shelterin complex, like mutations in PARN, which encodes a poly(A)-specific 30 exoribonuclease.8 In light of recent studies that have shown that PARN is important for 30 end processing and accumulation of hTR, this raises the possibility that other genes involved in telomerase biogenesis may be mutated in patients with TBDs. The collection of articles in this special issue of RNA Biology presents some of the current knowledge on telo-
meres and telomerase, and how it impacts our understanding of cancer, stem cells and telomeropathies. Altogether, these articles show that there is still much to learn about the various facets of telomerase biology, and on the role of novel non-coding RNAs such as TERRA in the maintenance of telomeres.
Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.
References 1. Podlevsky JD, Chen JJ-L. Evolutionary perspectives of telomerase RNA structure and function. RNA Biol 2016; 13:720-32; PMID:27359343; http://dx.doi.org/10.1080/15476286.2016.1205768 2. Webb CJ, Zakian VA. Telomerase RNA is more than a DNA template. RNA Biol 2016; 13:683-89; PMID:27245259; http://dx.doi. org/10.1080/15476286.2016.1191725 3. Arora R, Azzalin CM. Telomere elongation chooses TERRA ALTernatives. RNA Biol 2015; 12:938-41; PMID:26158306; http://dx.doi.org/ 10.1080/15476286.2015.1065374 4. Wang Z, Lieberman PM. The crosstalk of telomere dysfunction and inflammation through cell-free TERRA containing exosomes. RNA Biol 2016; 13:690-95; PMID:27351774; http://dx.doi.org/ 10.1080/15476286.2016.1203503 5. Fuhrmann G, J€ onsson F, Weil PP, Postberg J, Lipps HJ. RNA-template dependent de novo telomere addition. RNA Biol 2016; 13:733-39; PMID:26786510; http://dx.doi.org/10.1080/15476286.2015.1134414 6. Rousseau P, Autexier C. Telomere biology: Rationale for diagnostics and therapeutics in cancer. RNA Biol 2015; 12:1078-82; PMID:26291128; http://dx.doi.org/10.1080/15476286.2015.1081329 7. Teichroeb JH, Kim J, Betts DH. The role of telomeres and telomerase reverse transcriptase isoforms in pluripotency induction and maintenance. RNA Biol 2016; 13:707-19; PMID:26786236; http://dx.doi.org/ 10.1080/15476286.2015.1134413 8. Bertuch AA. The molecular genetics of the telomere biology disorders. RNA Biol 2016; 13:696-706; PMID:26400640; http://dx.doi.org/ 10.1080/15476286.2015.1094596
