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FLASH GENE

Symbol

TERT

contributors: mct/ - updated : 11-09-2019

HGNC name	telomerase reverse transcriptase
HGNC id	11730

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	virus associated
STRUCTURE	41.88 kb     16 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter (TATA box)
	cytosine-phosphate-guanine/HTF
	Binding site   transcription factor
motif	repetitive sequence   other
text structure	consensus binding sites and CMYc binding site
	a VNTR in intron 6
	E box in the promoter
	promoter region between -1623 and -1047 was responsible of its transcriptional suppression )
	TERT promoter has been shown to promote TERT gene expression selectively in tumor cells but not in normal cells
	promoter contains potential responsible elements for several direct and indirect negative transcriptional regulators, including Sp1/Sp3, AP1, WT1, MZF-2, CTCF, Mad1, Menin
	MCRS1 binds to the TERT proximal promoter
	promoter is regulated by multiple transcription factors (TFs) and its activity is dependent on the chromatin environment
	KLF2 represses TERT transcription by binding to the putative promoter element

MAPPING

cloned

Y

linked

N

status

confirmed

Map	pter - [WI-9907 - D5S678 - D5S417 ] - cen
Text	[TERT ]

RNA

TRANSCRIPTS	type	messenger

text	alternatively spliced variants resulting in exon(s) deletion, insertion, unspliced intron insertion or both (PMID: 9328464)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_198253 16 splicing 4018 NP_937983 126 1132 - 2013 23933091 isoform 1 NM_198255 16 splicing 3982 NP_937986 125 1120 - 2013 23933091 isoform 2

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine small intestine         stomach         Lymphoid/Immune lymph node       highly   thymus       moderately Reproductive female system ovary       Respiratory lung       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier/lining

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune T cell null (stem cell)

cell lineage
cell lines	epithelial cancer cell lines, many immortal cell lines
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal domain (TEN) that is important for activity and processivity, involved in conformational changes required to position the 3prime-end of the primer in the active site during nucleotide addition, a function which is distinct from the role of the TEN domain in providing DNA binding affinity
	a reverse transcriptase domain (RT)
	AAs 965-981 constitute an active nucleolar-targeting signal (NTS) essential for mediating TERT nucleolar localization

conjugated

RiboP

HOMOLOGY

interspecies	homolog to rattus Tert (64.42 pc)
	homolog to murine Tert (64.32 pc)

Homologene

FAMILY	reverse transcriptase family
	telomerase subfamily

CATEGORY

enzyme , DNA associated , protooncogene

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome,telomere
	intracellular,nucleus,nucleolus
text	restricted to the nucleus, had an antiapoptotic effect
	mitochondrial, induces apoptosis after oxidative stress
	nucleolar localization is unrelated to telomerase function in cells
	in primary cells, is released into the nucleoplasm during the late S/G2 stage of the cell cycle, coincident with the replication of telomeres
	NVL interacts and co-localizes with TERT in the nucleolus, and TERT was predominantly co-localized with NVL2 in the nucleolus
	TERT shuttles from the nucleus into mitochondria upon oxidative stress in cancer cells

basic FUNCTION	playing a crucial role in the immortality of tumor cells
	involved in telomere maintenance and participating in the regulation of cell proliferation and replicative lifespan
	putative upregulated c-Myc target gene
	critical determinant in the mobilization of epidermal stem cells
	essential component of telomerase production and of carcinogenesis
	promotes cellular and organismal survival independently of telomerase activity
	FEN1 and TERT complex could be participating in crucial events at telomeres, and understanding the role of this complex can pave way for telomerase based cancer therapeutics
	essential role of TERT, and TERC in the hematopoietic system sugesting that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall telomere shortening, are nevertheless crucial to maintain telomere homeostasis with age
	activation of TERT is required for the maintenance of telomere length in cancer cells
	TERT and TERC exert both reverse transcriptase-related (canonical) and noncanonical functions to affect tumor genome evolution through suppression or induction of polyploidization
	telomere-independent role for telomerase as a transcriptional modulator of the NFKB signaling pathway and a possible contributor to cancer development and progression
	TERT, a catalytic component of telomerase, plays dual roles in the TERF1 steady state pathway
	novel function of TERT in telomere length regulation
	its expression would function in counteracting against the stress because over-expression of TERT diminished ER stress-induced cell death
	TPP1 and the TEN domain of the telomerase catalytic subunit TERT regulate telomerase recruitment

CELLULAR PROCESS	cell life, cell death/apoptosis
	cell life, antiapoptosis
	nucleotide, replication

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	component of the telomerase complex, associating with NOLA1, NOLA2, NOLA3, NOLA4
	forming with RMRP a ribonucleoprotein complex that has RNA-dependent RNA polymerase activity and produces double-strand RNAs
	FEN1 forms a complex with telomerase in a cell cycle dependent manner

INTERACTION

DNA

RNA	interacting with RMRP

small molecule

protein	binding to TERC
	association with PINX1 within nucleoli might be through an indirect interaction and is mediated by a novel domain within the central region of PINX (interaction between PINX1 and TERT within the nucleolus might constitute a rapid responsive mechanism on telomerase functional modulation, important for cellular homeostasis)
	interacting with SMYD3 (direct target of SMYD3 contributing to a SMYD3-mediated cellular transformation)
	binding to SMAD3
	interacting with SMARCA4 and activating Wnt/beta catenin signalling pathway
	one of the major targets of KLF4 in cancer and stem cells to maintain long-term proliferation potential
	interacting with a putative gene on human chromosome 5 contributes to its transcriptional silencing
	RUVBL2 is a transcriptional regulator of TERT
	FEN1 and telomerase association occurs throughout the S phase, with the maximum association in the mid S phase (
	DKC1 promotes TERT stability, endorsing the development of TERT supplementation strategies for the treatment of DKC1
	NVL2 associates with catalytically competent telomerase through an interaction with TERT, and this association could be specific
	TCF4 may bind to TERT promoter and activate TERT gene transcription upon forming a transcriptional complex with CTNNB1
	during the cell cycle, DYRK2 interacts with TERT at the G2/M phase and induces degradation
	DYRK2-associated DDB1-UBR5-VPRBP E3 ligase inhibits telomerase by TERT degradation
	is a direct target of the HH signaling pathway, and HH signaling regulates telomerase reverse transcriptase in cancer cells
	MCRS1 is a negative regulator of TERT expression and telomerase activity
	DEK emerges as an TERT repressor shared by various leukemia subtypes and seems involved in the deregulation of numerous genes associated with leukemogenesis
	PINX1 may maintain telomere integrity by regulating TERF1 stability and TERT may act as both a positive and a negative regulator of TERF1 homeostasis in a PINX1-dependent manner
	CPSF4 plays a critical role in the regulation of TERT expression and lung tumorigenesis and may be a new prognosis factor in lung adenocarcinomas
	interaction between TERT and PTTG1 by association of XRCC6 might be important for the enhancement of the limited self-renewal activity of MSCs and for understanding the regulatory mechanisms of self-renewal
	FOXO3 functions downstream of SIRT1 and prevents the induction of cellular senescence by enhancing TERT gene expression
	MYC functioned in maintaining chromatin-dependent repression of the TERT gene in addition to activating its promoter
	stability of PINX1 is maintained in nucleolus in the presence of TERT, suggesting a role of TERT in the regulation of PINX1 steady-state levels
	PTBP1 interacts with TERT pre-mRNA in a NOVA1 dependent fashion
	CPSF4 facilitated colorectal tumorigenesis and development partially through transcriptionally regulating TERT expression by cooperating with NFKB1 and co-anchoring at TERT promoter -321 to -234 fragment
	RBM10 regulates human TERT gene splicing and inhibits pancreatic cancer progression
	NKX2.4 regulates TERT and CLPTM1L expression

cell & other

REGULATION

induced by

MYC

inhibited by

MAD1L1

repressed by	MEN1
		SIP1
		PRKCD, which function in telomerase reverse transcriptase (TERT) gene repression

Other	regulated by DNA methylation of the promoter region
	regulated by FRK
	regulated by truncated USF2 during lymphocyte activation
	condensed chromatin environment plays a role in silencing TERT during cell differentiation
	strongly repressed during differentiation of cells

ASSOCIATED DISORDERS

corresponding disease(s)

DKC3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral       gain of function in cancer tumoral     --over   with BIRC5 in soft tissue sarcoma with very poor outlook constitutional somatic mutation       impair telomerase activity by haploinsufficiency and may be risk factors for marrow failure constitutional     --over   increases stem-like properties and decreases spontaneous differentiation in human mesenchymal stem cell lines tumoral somatic mutation       in 71p 100 of melanomas (pMID: 23348506) tumoral germinal mutation       mutations creating Ets/TCF binding motifs in the TERT promoter in familial melanoma tumoral fusion       IRX2-TERT fusion in clear cell sarcoma of the kidney

Susceptibility

susceptibility to idiopathic pulmonary fibrosis to lung adenocarcinoma to squamous cell carcinoma of the head and neck to haematological malignancies, including myelodysplastic syndrome and acute myeloid leukaemia as well as chronic lymphocytic leukaemia to age-related disease idiopathic pulmonary fibrosis with telomere shortening to testicular germ cell tumor (TGCT) to variation of telomere length, to Telomere length (TL) shortening to uveal melanoma (UM)

Variant & Polymorphism SNP	significant association of an SNP in intron 2 of the TERT gene (rs2736100), which encodes a reverse transcriptase that is a component of a telomerase, to idiopathic pulmonary fibrosis
	variants in TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short
	SNPs of TERT-rs2736098 (C > T) and CLPTM1L-rs401681(C > T), may be associated with a reduced risk of squamous cell carcinoma of the head and neck, particularly for their combined effect
	rs2736100 associated with risk of lung adenocarcinoma
	association between genetic marker rs2735940 and TGCT risk
	variants associated with increased risk of haematological malignancies, including myelodysplastic syndrome and acute myeloid leukaemia as well as chronic lymphocytic leukaemia
	two non-synonymous substitutions in the catalytic domain of the telomerase reverse transcriptase gene TERT: V791I and V867M increasing the risk of age-related disease idiopathic pulmonary fibrosis with telomere shortening
	in UM rs452384 is a functional variant that mediates allele-specific binding of the NKX2.4 nuclear factor and the transcriptional activity of the region, including TERT and CLPTM1L
	exposure to polycyclic aromatic hydrocarbons (PAHs) can accelerate the TL shortening and this effect can be modified by TERT-CLPTM1L variants

Candidate gene
Marker
Therapy target	TERT gene-based drug design may be useful in the treatment of leukemic myelopoiesis

ANIMAL & CELL MODELS

mouse lacking telomerase activity display decrease proliferation in testis and increased apoptosis