端粒与端粒酶的结构及调节
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摘要
端粒作为维持染色体完整性的主要因素,在衰老与肿瘤抑制机制中是一个必不可少的活性调节因素,是与癌症高度相关的;在正常体细胞中,当端粒缩短至一定极限时(即经过大约50-70次的细胞分裂)细胞基因变的极不稳定导致人类组织和细胞衰老直至凋亡;但是,一些逃脱凋亡的细胞几乎普遍表达一种核糖核蛋白,端粒酶(一种细胞逆转录酶,增加新的DNA到位于染色体末端的端粒上面),从而维护稳定但短的端粒;而在大多数癌症细胞、造血干细胞、生殖细胞中,端粒、端粒酶是维持染色体稳定的主要因素,因此二者不仅与细胞衰老有直接关系,还与肿瘤的发生发展有密切的关系。端粒酶做为端粒长度维持的主要调节因素,为抗衰老、肿瘤治疗提供了新的靶标。本文综述了端粒长度维持的相关机制,端粒酶组成与调节的最新进展;并讨论了最近通过抑制端粒酶活性来治疗癌症的可能性。
Telomeres,as a major factor of maintaining chromosomal integrity,is an essential activity of regulatory factors of aging and tumor suppression mechanism,and are highly associated with cance;in normal somatic cells,when telomeres shorten to a certain limit(ie after about 50-70times a cell division)cell gene becomes unstable causing human tissue and cell senescence until death;but some escape apoptotic cells almost universally express a ribonucleoprotein,telomerase(a cellular reversal transcriptase,adding new DNA to telomerestheends of chromosomes),in order to maintain steady but short telomeres;while in most cancer cells,hematopoietic stem cells,germ cells,telomeres,telomerase are major factors in maintaining chromosome stability,not only with cellular senescence direct relationship is also closely related to tumor development。Telomerase is a major regulator factors of the telomere length,which provide new targets for anti-aging and cancer treatment。Here we review mechanisms of maintain telomere length and the latest developments of telomerase composition、regulation。
Telomeres,as a major factor of maintaining chromosomal integrity,is an essential activity of regulatory factors of aging and tumor suppression mechanism,and are highly associated with cance;in normal somatic cells,when telomeres shorten to a certain limit(ie after about 50-70times a cell division)cell gene becomes unstable causing human tissue and cell senescence until death;but some escape apoptotic cells almost universally express a ribonucleoprotein,telomerase(a cellular reversal transcriptase,adding new DNA to telomerestheends of chromosomes),in order to maintain steady but short telomeres;while in most cancer cells,hematopoietic stem cells,germ cells,telomeres,telomerase are major factors in maintaining chromosome stability,not only with cellular senescence direct relationship is also closely related to tumor development。Telomerase is a major regulator factors of the telomere length,which provide new targets for anti-aging and cancer treatment。Here we review mechanisms of maintain telomere length and the latest developments of telomerase composition、regulation。
引文
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[24]Ladetto,M.,et al.,Telomere length correlates with histopathogenesis according to the germinal center in mature B-cell lymphoproliferative disorders[J].Blood,2004.103(12):p.4644-9
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[26]Taiwo,B.,R.L.Murphy and C.Katlama,Novel antiretroviral combinations in treatment-experienced patients with HIV infection:rationale and results[J].Drugs,2010.70(13):p.1629-42
[27]Ouellette,M.M.,W.E.Wright and J.W.Shay,Targeting telomerase-expressing cancer cells[J].J Cell Mol Med,2011.15(7):p.1433-42
[2]Wu,X.M,W.R.Tang and Y.Luo,[ALT-alternative lengthening of telomere][J].Yi Chuan,2009,31(12):p.1185-91
[3]Donate,L.E,M.A.Blasco,et al.Telomeres in cancer and ageing[J].Philos Trans R Soc Lond B Biol Sci,2011,366(1561):p.76-84
[4]Diotti,R,D.Loayza.Shelterin complex and associated factors at human telomeres.[J].Nucleus,2011,2(2):p.119-35
[5]Bianchi,A,D.Shore.How telomerase reaches its end:mechanism of telomerase regulation by the telomeric complex[J].Mol Cell,2008.31(2):p.153-65
[6]Bryan,T.M.Telomere elongation in immortal human cells without detectable telomerase activity[J].EMBO J,1995,14(17):p.4240-8
[7]Sampathi,S.,W.Chai.Telomere replication:poised but puzzling[J].J Cell Mol Med,2011,15(1):p.3-13
[8]吴晓明,唐文如,罗瑛,等.ALT——端粒延长替代机制[J].遗传,2009,31(12):1185―1191
[9]Codd,V.Common variants near TERC are associated with mean telomere length[J].Nat Genet,2010,42(3):p.197-9
[10]Levy,D.Genome-wide association identifies OBFC1as a locus involved in human leukocyte telomere biology[J].Proc Natl Acad Sci U S A,2010,107(20):p.9293-8
[11]Mangino.Genome-wide meta-analysis points to CTC1and ZNF676as genes regulating telomere homeostasis in humans[J].Hum Mol Genet,2012
[12]Zvereva,M.I.,D.M.Shcherbakova and O.A.Dontsova,Telomerase:structure,functions,and activity regulation[J].Biochemistry(Mosc),2010,75(13):p.1563-83
[13]黄世杰,魏霞.端粒酶和癌症治疗[J].国际药学研究杂志,2008
[14]Chang,J.T.,et al.,Differential regulation of telomerase activity by six telomerase subunits[J].Eur J Biochem,2002.269(14):p.3442-50
[15]Cifuentes-Rojas,C.and D.E.Shippen,Telomerase regulation[J].Mutat Res,2012.730(1-2):p.20-7
[16]Akiyama,B.M.and M.D.Stone,Structural biology:A solution to the telomerase puzzle[J].2013.496(7444):p.177-178
[17]Kanaya,T.,et al.,hTERT is a critical determinant of telomerase activity in renal-cell carcinoma[J].Int J Cancer,1998.78(5):p.539-43
[18]Kyo,S.,et al.,Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers[J].Cancer Sci,2008.99(8):p.1528-38
[19]Kirkpatrick,K.L.,et al.,hTERT expression in human breast cancer and non-cancerous breast tissue:correlation with tumour stage and c-Myc expression[J].Breast Cancer Res Treat,2003.77(3):p.277-84
[20]Fujimoto,K.,et al.,Identification and characterization of negative regulatory elements of the human telomerase catalytic subunit(hTERT)gene promoter:possible role of MZF-2in transcriptional repression of hTERT[J].Nucleic Acids Res,2000.28(13):p.2557-62
[21]Shats,I.,et al.,p53-dependent down-regulation of telomerase is mediated by p21waf1[J].J Biol Chem,2004.279(49):p.50976-85
[22]Zhao,Y.,et al.,Processive and distributive extension of human telomeres by telomerase under homeostatic and nonequilibrium conditions[J].Mol Cell,2011.42(3):p.297-307
[23]Wojtyla,A.,M.Gladych and B.Rubis,Human telomerase activity regulation[J].Mol Biol Rep,2011.38(5):p.3339-49
[24]Ladetto,M.,et al.,Telomere length correlates with histopathogenesis according to the germinal center in mature B-cell lymphoproliferative disorders[J].Blood,2004.103(12):p.4644-9
[25]Stewart,S.A.and A.A.Bertuch,The role of telomeres and telomerase in cancer research[J].Cancer Res,2010.70(19):p.7365-71
[26]Taiwo,B.,R.L.Murphy and C.Katlama,Novel antiretroviral combinations in treatment-experienced patients with HIV infection:rationale and results[J].Drugs,2010.70(13):p.1629-42
[27]Ouellette,M.M.,W.E.Wright and J.W.Shay,Targeting telomerase-expressing cancer cells[J].J Cell Mol Med,2011.15(7):p.1433-42