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Cancer Discov. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: Cancer Discov. 2016 November ; 6(11): 1212–1214. doi:10.1158/2159-8290.CD-16-1050.
TERT Promoter Mutations Enhance Telomerase Activation by Long-range Chromatin Interactions Jaewon Min and Jerry W. Shay* Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas, 75390-9039, USA
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Summary While single nucleotide somatic mutations in the proximal promoter of the human telomerase reverse transcriptase (TERT) gene create novel consensus sequences for transcription factors that enhance TERT expression, the precise mechanism of how telomerase is re-activated in cancer cells remains poorly understood. In this issue, Ak1nc1lar and colleagues (1) identify a potential mechanism of TERT reactivation that is mediated by a novel long-range chromatin interactions between the TERT promoter on chromosome 5p and a 300 kb upstream region. This permits recruitment of the transcription factor GABPA in mutant TERT promoters but not in wild-type promoters.
Author Manuscript
Telomeres in mammals are chromosome ends that are composed of thousands of the canonical repetitive sequence TTAGGG (2). Telomeres shorten with each cell division due to the end replication problem (incomplete lagging strand DNA synthesis at the end) and postreplication end processing (telomeric overhang generation processes). In proliferating stem and germ-line cells, telomeres can be partially maintained by the cellular reverse transcriptase, termed telomerase. Telomerase adds new TTAGGG repeats onto the telomeric overhangs, but due to lack or insufficient telomerase activity, human somatic cells can only divide until at least some telomere ends become critically shortened (uncapped and recognized as a DNA double strand break). Most premalignant human lesions harbor very short telomeres and it is generally thought that the repression of telomerase and progressive telomeres shortening may have evolved in large long-lived species as an initial anti-tumor protective mechanism (2). To continue to divide, pre-malignant cancer cells need to acquire a telomere maintenance mechanism during neoplastic transformation. The vast majority of human cancers (>85%) maintain their telomere length via telomerase reactivation (2). All human tissues express the functional telomerase templating RNA component (TERC), whereas most human adult tissues do not express telomerase reverse transcriptase (TERT). During early human fetal development telomerase is expressed and, in a tissue specific manner, the TERT gene becomes silenced. While the regulation of TERT is complex and
Author Manuscript *
Corresponding author: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9039, Tel: 214-648-4201, Fax: 214-648-5814, [email protected]. Disclosure of Potential Conflicts of Interest The authors disclose no potential conflicts of interest.
Min and Shay
Page 2
Author Manuscript
involves transcriptional, post-transcriptional and epigenetic modifications, the precise mechanism of activation of telomerase in cancer has not been resolved.
Author Manuscript
The TERT gene has a GC rich core promoter containing CpG islands that are mostly methylated in normal cells (1). The hypermethylation of the TERT core promoter is believed to be one of the major mechanisms for TERT repression but what changes the methylation status during fetal development is not known. In addition, the TERT promoter does not have typical transcriptional elements such as TATA boxes or CCAAT boxes; instead it contains GC-boxes, which are the consensus binding sites for the transcription factor Sp1. Masking of the Sp1 binding site by G-quadruplex formation in GC-boxes may be another mechanism for TERT promoter repression. Thus, transcriptional up-regulation or reactivation of the TERT gene is a critical step in tumorigenesis and multiple mechanisms have been proposed for reactivating TERT gene in cancer. These include mutation or deletion in the TERT promoter, TERT gene amplification, epigenetic alterations, and TERT gene alternative splicing factors (2). How cancer cells activate the silenced TERT gene still remains largely unknown.
Author Manuscript
From genetic linkage analysis and whole-genome sequencing, it has been recently reported that TERT gene can be reactivated by proximal promoter mutation (3,4). These are single nucleotide mutations in the proximal promoter of the TERT gene; cytosine to thymidine transition at −124 bp and −146 bp upstream of the translation start site. These TERT promoter mutations are very close to the transcription start site of the TERT gene (−46 bp and −68 bp upstream of transcription start site). Importantly, these are also located in the GC-boxes in the TERT core promoter (−90 bp to −22 bp upstream of transcription start site). These two TERT promoter mutations (−124C>T, −146C>T) are now considered among the most common noncoding mutations in cancer. For example, monoallelic TERT promoter mutations are common in melanomas (~85%), glioblastomas (~84%), hepatocellular carcinomas (~44%), liposarcomas (~79%) and urothelial cancers (~47%) (3-5). However, TERT promoter mutations are much less common (
Cancer Discov. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: Cancer Discov. 2016 November ; 6(11): 1212–1214. doi:10.1158/2159-8290.CD-16-1050.
TERT Promoter Mutations Enhance Telomerase Activation by Long-range Chromatin Interactions Jaewon Min and Jerry W. Shay* Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas, 75390-9039, USA
Author Manuscript
Summary While single nucleotide somatic mutations in the proximal promoter of the human telomerase reverse transcriptase (TERT) gene create novel consensus sequences for transcription factors that enhance TERT expression, the precise mechanism of how telomerase is re-activated in cancer cells remains poorly understood. In this issue, Ak1nc1lar and colleagues (1) identify a potential mechanism of TERT reactivation that is mediated by a novel long-range chromatin interactions between the TERT promoter on chromosome 5p and a 300 kb upstream region. This permits recruitment of the transcription factor GABPA in mutant TERT promoters but not in wild-type promoters.
Author Manuscript
Telomeres in mammals are chromosome ends that are composed of thousands of the canonical repetitive sequence TTAGGG (2). Telomeres shorten with each cell division due to the end replication problem (incomplete lagging strand DNA synthesis at the end) and postreplication end processing (telomeric overhang generation processes). In proliferating stem and germ-line cells, telomeres can be partially maintained by the cellular reverse transcriptase, termed telomerase. Telomerase adds new TTAGGG repeats onto the telomeric overhangs, but due to lack or insufficient telomerase activity, human somatic cells can only divide until at least some telomere ends become critically shortened (uncapped and recognized as a DNA double strand break). Most premalignant human lesions harbor very short telomeres and it is generally thought that the repression of telomerase and progressive telomeres shortening may have evolved in large long-lived species as an initial anti-tumor protective mechanism (2). To continue to divide, pre-malignant cancer cells need to acquire a telomere maintenance mechanism during neoplastic transformation. The vast majority of human cancers (>85%) maintain their telomere length via telomerase reactivation (2). All human tissues express the functional telomerase templating RNA component (TERC), whereas most human adult tissues do not express telomerase reverse transcriptase (TERT). During early human fetal development telomerase is expressed and, in a tissue specific manner, the TERT gene becomes silenced. While the regulation of TERT is complex and
Author Manuscript *
Corresponding author: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9039, Tel: 214-648-4201, Fax: 214-648-5814, [email protected]. Disclosure of Potential Conflicts of Interest The authors disclose no potential conflicts of interest.
Min and Shay
Page 2
Author Manuscript
involves transcriptional, post-transcriptional and epigenetic modifications, the precise mechanism of activation of telomerase in cancer has not been resolved.
Author Manuscript
The TERT gene has a GC rich core promoter containing CpG islands that are mostly methylated in normal cells (1). The hypermethylation of the TERT core promoter is believed to be one of the major mechanisms for TERT repression but what changes the methylation status during fetal development is not known. In addition, the TERT promoter does not have typical transcriptional elements such as TATA boxes or CCAAT boxes; instead it contains GC-boxes, which are the consensus binding sites for the transcription factor Sp1. Masking of the Sp1 binding site by G-quadruplex formation in GC-boxes may be another mechanism for TERT promoter repression. Thus, transcriptional up-regulation or reactivation of the TERT gene is a critical step in tumorigenesis and multiple mechanisms have been proposed for reactivating TERT gene in cancer. These include mutation or deletion in the TERT promoter, TERT gene amplification, epigenetic alterations, and TERT gene alternative splicing factors (2). How cancer cells activate the silenced TERT gene still remains largely unknown.
Author Manuscript
From genetic linkage analysis and whole-genome sequencing, it has been recently reported that TERT gene can be reactivated by proximal promoter mutation (3,4). These are single nucleotide mutations in the proximal promoter of the TERT gene; cytosine to thymidine transition at −124 bp and −146 bp upstream of the translation start site. These TERT promoter mutations are very close to the transcription start site of the TERT gene (−46 bp and −68 bp upstream of transcription start site). Importantly, these are also located in the GC-boxes in the TERT core promoter (−90 bp to −22 bp upstream of transcription start site). These two TERT promoter mutations (−124C>T, −146C>T) are now considered among the most common noncoding mutations in cancer. For example, monoallelic TERT promoter mutations are common in melanomas (~85%), glioblastomas (~84%), hepatocellular carcinomas (~44%), liposarcomas (~79%) and urothelial cancers (~47%) (3-5). However, TERT promoter mutations are much less common (
