Restricted accessResearch articleFirst published online 2017-08
Comprehensive Analysis of Interaction Networks of Telomerase Reverse Transcriptase with Multiple Bioinformatic Approaches: Deep Mining the Potential Functions of Telomere and Telomerase
Telomerase reverse transcriptase (TERT) is the protein component of telomerase complex. Evidence has accumulated showing that the nontelomeric functions of TERT are independent of telomere elongation. However, the mechanisms governing the interaction between TERT and its target genes are not clearly revealed. The biological functions of TERT are not fully elucidated and have thus far been underestimated. To further explore these functions, we investigated TERT interaction networks using multiple bioinformatic databases, including BioGRID, STRING, DAVID, GeneCards, GeneMANIA, PANTHER, miRWalk, mirTarBase, miRNet, miRDB, and TargetScan. In addition, network diagrams were built using Cytoscape software. As competing endogenous RNAs (ceRNAs) are endogenous transcripts that compete for the binding of microRNAs (miRNAs) by using shared miRNA recognition elements, they are involved in creating widespread regulatory networks. Therefore, the ceRNA regulatory networks of TERT were also investigated in this study. Interestingly, we found that the three genes PABPC1, SLC7A11, and TP53 were present in both TERT interaction networks and ceRNAs target genes. It was predicted that TERT might play nontelomeric roles in the generation or development of some rare diseases, such as Rift Valley fever and dyscalculia. Thus, our data will help to decipher the interaction networks of TERT and reveal the unknown functions of telomerase in cancer and aging-related diseases.
BlackburnEH, EpelES, LinJ. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science, 2015; 350:1193–1198.
BoersmaV, MoattiN, Segura-BayonaS, PeuscherMH, van der TorreJ, WeversBA, OrthweinA, DurocherD, JacobsJJ. MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection. Nature, 2015; 521:537–540.
7.
HayashiMT, CesareAJ, RiveraT, KarlsederJ. Cell death during crisis is mediated by mitotic telomere deprotection. Nature, 2015; 522:492–496.
8.
SchmidtJC, ZaugAJ, CechTR. Live cell imaging reveals the dynamics of telomerase recruitment to telomeres. Cell, 2016; 166:1188–1197.e9.
NoëlJF, WellingerRJ. Exposing secrets of telomere-telomerase encounters. Cell, 2012; 150:453–454.
17.
PfingstenJS, GoodrichKJ, TaabazuingC, OuenzarF, ChartrandP, CechTR. Mutually exclusive binding of telomerase RNA and DNA by Ku alters telomerase recruitment model. Cell, 2012; 148:922–932.
SaretzkiG. Extra-telomeric functions of human telomerase: Cancer, mitochondria and oxidative stress. Curr Pharm Des, 2014; 20:6386–6403.
21.
MiwaS, CzapiewskiR, WanT, BellA, HillKN, von ZglinickiT, SaretzkiG. Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mitochondria. Aging (Albany NY), 2016; 8:2551–2567.
22.
Ale-AghaN, Dyballa-RukesN, JakobS, AltschmiedJ, HaendelerJ. Cellular functions of the dual-targeted catalytic subunit of telomerase, telomerase reverse transcriptase—Potential role in senescence and aging. Exp Gerontol, 2014; 56:189–193.
23.
WuXQ, HuangC, HeX, TianYY, ZhouDX, HeY, LiuXH, LiJ. Feedback regulation of telomerase reverse transcriptase: New insight into the evolving field of telomerase in cancer. Cell Signal, 2013; 25:2462–2468.
SahaB, ZitnikG, JohnsonS, NguyenQ, RisquesRA, MartinGM, OshimaJ. DNA damage accumulation and TRF2 degradation in atypical Werner syndrome fibroblasts with LMNA mutations. Front Genet, 2013; 4:129.
SzklarczykD, FranceschiniA, WyderS, ForslundK, HellerD, Huerta-CepasJ, SimonovicM, RothA, SantosA, TsafouKP, KuhnM, BorkP, JensenLJ, von MeringC.STRING v10: Protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res, 2015; 43:D447–D452.
35.
KohlM, WieseS, WarscheidB. Cytoscape: Software for visualization and analysis of biological networks. Methods Mol Biol, 2011; 696:291–303.
Wong Nathan and Wang Xiaowei. miRDB: An online resource for microRNA target prediction and functional annotations. Nucleic Acids Res, 2015; 43:D146–D152.
43.
XiaoweiW. Improving microRNA target prediction by modeling with unambiguously identified microRNA-target pairs from CLIP-ligation studies. Bioinformatics, 2016; 32:1316–1322.
44.
FanY, SiklenkaK., AroraSK., RibeiroP., KimminsS. and XiaJ. miRNet—Dissecting miRNA-target interactions and functional associations through network-based visual analysis. Nucleic Acids Res, 2016; 44:W135–W141.
45.
FrommB, BillippT, PeckLE, JohansenM, TarverJE, KingBL, NewcombJM, SempereLF, FlatmarkK, HovigE, PetersonKJ. A uniform system for the annotation of vertebrate microRNA genes and the evolution of the human microRNAome. Annu Rev Genet, 2015; 49:213–242.
46.
Bernardes de JesusB, BlascoMA. Potential of telomerase activation in extending health span and longevity. Curr Opin Cell Biol, 2012; 24:739–743.
47.
ArndtGM, MacKenzieKL. New prospects for targeting telomerase beyond the telomere. Nat Rev Cancer, 2016; 16:508–524.
48.
González-GiraldoY, ForeroDA, EcheverriaV, GonzalezJ, Ávila-RodriguezM, Garcia-SeguraLM, BarretoGE. Neuroprotective effects of the catalytic subunit of telomerase: A potential therapeutic target in the central nervous system. Ageing Res Rev, 2016; 28:37–45.
49.
MadlalaP, SinghR, AnP, WernerL, MlisanaK, Abdool KarimSS, WinklerCA, NdunguT. Association of polymorphisms in the regulatory region of the cyclophilin a gene (PPIA) with gene expression and HIV/AIDS disease progression. J Acquir Immune Defic Syndr, 2016; 72:465–473.
50.
XuJ, KhinchaPP, GiriN, AlterBP, SavageSA, WongJM. Investigation of chromosome X inactivation and clinical phenotypes in female carriers of DKC1 mutations. Am J Hematol, 2016; 91:1215–1220.
51.
ArancioW, PizzolantiG, GenoveseSI, BaiamonteC, GiordanoC. Competing endogenous RNA and interactome bioinformatic analyses on human telomerase. Rejuvenation Res, 2014; 17:161–167.
52.
StupflerB, BirckC, SéraphinB, MauxionF. BTG2 bridges PABPC1 RNA-binding domains and CAF1 deadenylase to control cell proliferation. Nat Commun, 2016; 7:10811.
53.
KatzenellenbogenRA, Vliet-GreggP, XuM, GallowayDA. Cytoplasmic poly(A) binding proteins regulate telomerase activity and cell growth in human papillomavirus type 16 E6-expressing keratinocytes. J Virol, 2010; 84:12934–12944.
54.
ListermanI, SunJ, GazzanigaFS, LukasJL, BlackburnEH. The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibitstelomerase activity but protects from apoptosis. Cancer Res, 2013; 73:2817–2828.
55.
SehmT, RauhM, WiendieckK, BuchfelderM, EyüpogluIY, SavaskanNE. Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis. Oncotarget, 2016; 7:74630–74647.
56.
ZhangRR, PointerKB, KuoJS. Excitotoxic SLC7A11 Expression is a marker of poor glioblastoma survival and a potential therapeutic target. Neurosurgery, 2015; 77:N16–N17.
57.
Diaz-LagaresA, CrujeirasAB, Lopez-SerraP, SolerM, SetienF, GoyalA, SandovalJ, HashimotoY, Martinez-CardúsA, GomezA, HeynH, MoutinhoC, EspadaJ, VidalA, PaúlesM, GalánM, SalaN, AkiyamaY, Martínez-IniestaM, FarréL, VillanuevaA, GrossM, DiederichsS, GuilS, EstellerM. Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer. Proc Natl Acad Sci U S A, 2016; pii:201608585.
58.
TanakaH, BeamMJ, CaruanaK. The presence of telomere fusion in sporadic colon cancer independently of disease stage, TP53/KRAS mutation status, mean telomere length, and telomerase activity. Neoplasia, 2014; 16:814–823.
59.
CardinR, PiciocchiM, TieppoC, MaddaloG, ZaninottoG, MescoliC, RuggeM, FarinatiF. Oxidative DNA damage in Barrett mucosa: Correlation with telomeric dysfunction and p53 mutation. Ann Surg Oncol, 2013; 20Suppl 3:S583–S589.
60.
SongG, WangR, GuoJ, LiuX, WangF, QiY, WanH, LiuM, LiX, TangH. miR-346 and miR-138 competitively regulate hTERT in GRSF1- and AGO2-dependent manners, respectively. Sci Rep, 2015; 5:15793.
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