Telomere, the nucleoprotein structure at the end of eukaryotic linear chromosomes is indispensable for maintaining the genome stability. Telomeric DNA loss is apparent with each cell division, which marks an endpoint ...Telomere, the nucleoprotein structure at the end of eukaryotic linear chromosomes is indispensable for maintaining the genome stability. Telomeric DNA loss is apparent with each cell division, which marks an endpoint to the indefinite replication of the cell by causing replicative senescence that may lead to the programmed cell death. The loss of telomere is normal in cell division and as such after 20 - 40 divisions, telomere becomes too short to facilitate the capping function. Telomere uncapping or chromosomal free end causes a potential threat to the genomic stability and thus leads to the accumulation of chromosomal abnormalities that have been known to play a role in aging and cancer. Telomerase, the ribonucleoprotein complex, and its accessory proteins are required to maintain the telomere sequence. Telomerase plays a key role in maintaining the length of telomere by adding G-rich repeat sequences. Its activity has been found to be quite high in the gametes, stem cells and most importantly tumor cells. Almost 85% of tumor cells compensate for telomere loss aided by telomerase-associated protein complex and shelter in complex or telosome. However, 5% - 10% of the cells undergo telomerase-independent mechanism. This review presents the molecular view of the telomere and telomerase along with its associated complex structures. It also discusses its contrasting role in causing cellular senescence and promoting tumorigenesis.展开更多
Background: Telomere length dysregulation plays a major role in cancer development and aging. Telomeres are maintained by a group of specialized genes known as shelterin and shelterin-associated proteins. In breast ca...Background: Telomere length dysregulation plays a major role in cancer development and aging. Telomeres are maintained by a group of specialized genes known as shelterin and shelterin-associated proteins. In breast cancer lines it has been shown that shelterin proteins are dysregulated thereby affecting the telomere stability and contributing to the neoplastic conversion of the mammary epithelial cells. Interestingly, the regulation of some of the shelterin genes is thought to be controlled epigenetically. Methods and Results: In this study, we set out to measure the effect of increased shelterin gene expression on telomere length in breast cancer cell line 21NT treated with 5-aza-2-deoxycytidine (5-aza-CdR) using known telomere length assays. We measured telomere lengths using: Telomere Restriction Fragment length (TRF), absolute quantitative-PCR and cytogenetic Interphase Quantitative Fluorescent in situ Hybridization (iQ-FISH). We found that non-cytotoxic levels of 5-aza-CdR affect telomere lengths by causing a significant and stable increase in telomere lengths of the breast cancer cell line. The increase in telomere lengths was consistently observed when various telomere length methods were used. Conclusions: Further investigation is required to understand the underlying mechanism involved, and the significance of telomere length elongation in relation to clinical outcome when epigenetic modifying drugs are utilized.展开更多
端粒保护蛋白1(protection of telomeres 1,POT1)几乎存在于所有真核生物中,是一种高度保守表达的蛋白质,它与一系列相关的端粒结合蛋白共同参与保护端粒的结构和功能。随着近年来研究的深入,POT1与端粒的结合特点以及保护端粒的机制有...端粒保护蛋白1(protection of telomeres 1,POT1)几乎存在于所有真核生物中,是一种高度保守表达的蛋白质,它与一系列相关的端粒结合蛋白共同参与保护端粒的结构和功能。随着近年来研究的深入,POT1与端粒的结合特点以及保护端粒的机制有了进一步的完善。此外,POT1对端粒长度的调节方式以及与肿瘤的发生、发展和细胞凋亡等关系也呈现出多样化。结合近几年的研究文献,对POT1的功能以及与其它相关蛋白的作用加以综述。展开更多
Telomeres, the ends of linear eukaryotic chromosomes, are tandem DNA repeats and capped by various telomeric proteins. These nucleoprotein complexes protect telomeres from DNA damage response （DDR）, recombination, a...Telomeres, the ends of linear eukaryotic chromosomes, are tandem DNA repeats and capped by various telomeric proteins. These nucleoprotein complexes protect telomeres from DNA damage response （DDR）, recombination, and end-to-end fusions, ensuring genome stability. The human telosome/shelterin complex is one of the best-studied telomere-associated protein complexes, made up of six core telomeric proteins TRF1, TRF2, TIN2, RAPI, POT1, and TPPI. TPP1, also known as adrenocortical dysplasia protein homolog （ACD）, is a putative mammalian homolog of TEBP-β and belongs to the oligonucleotide binding （OB）-fold-containing protein family. Three functional domains have been identified within TPP1, the N-terminal OB fold, the POT1 binding recruitment domain （RD）, and the carboxyl-terminal TIN2-interacting domain （TID）. TPP1 can interact with both POT1 and TIN2 to maintain telomere structure, and mediate telomerase recruitment for telomere elongation. These features have indicated TPP1 play an essential role in telomere maintenance. Here, we will review important findings that highlight the functional significance of TPP1, with a focus on its interaction with other telosome components and the telomerase. We will also discuss potential implications in disease therapies.展开更多
Pluripotent stem cells(PSCs)such as embryonic stem cells(ESCs),ESCs derived by somatic cell nuclear transfer(ntESCs),and induced pluripotent stem cells(iPSCs)have unlimited capacity for self-renewal and pluripotency a...Pluripotent stem cells(PSCs)such as embryonic stem cells(ESCs),ESCs derived by somatic cell nuclear transfer(ntESCs),and induced pluripotent stem cells(iPSCs)have unlimited capacity for self-renewal and pluripotency and can give rise to all types of somatic cells.In order to maintain their self-renewal and pluripotency,PSCs need to preserve their telomere length and homeostasis.In recent years,increasing studies have shown that telomere reprogramming is essential for stem cell pluripotency maintenance and its induced pluripotency process.Telomere-associated proteins are not only required for telomere maintenance in both stem cells,their extra-telomeric functions have also been found to be critical as well.Here,we will discuss how telomeres and telomere-associated factors participate and regulate the maintenance of stem cell pluripotency.展开更多
文摘Telomere, the nucleoprotein structure at the end of eukaryotic linear chromosomes is indispensable for maintaining the genome stability. Telomeric DNA loss is apparent with each cell division, which marks an endpoint to the indefinite replication of the cell by causing replicative senescence that may lead to the programmed cell death. The loss of telomere is normal in cell division and as such after 20 - 40 divisions, telomere becomes too short to facilitate the capping function. Telomere uncapping or chromosomal free end causes a potential threat to the genomic stability and thus leads to the accumulation of chromosomal abnormalities that have been known to play a role in aging and cancer. Telomerase, the ribonucleoprotein complex, and its accessory proteins are required to maintain the telomere sequence. Telomerase plays a key role in maintaining the length of telomere by adding G-rich repeat sequences. Its activity has been found to be quite high in the gametes, stem cells and most importantly tumor cells. Almost 85% of tumor cells compensate for telomere loss aided by telomerase-associated protein complex and shelter in complex or telosome. However, 5% - 10% of the cells undergo telomerase-independent mechanism. This review presents the molecular view of the telomere and telomerase along with its associated complex structures. It also discusses its contrasting role in causing cellular senescence and promoting tumorigenesis.
文摘Background: Telomere length dysregulation plays a major role in cancer development and aging. Telomeres are maintained by a group of specialized genes known as shelterin and shelterin-associated proteins. In breast cancer lines it has been shown that shelterin proteins are dysregulated thereby affecting the telomere stability and contributing to the neoplastic conversion of the mammary epithelial cells. Interestingly, the regulation of some of the shelterin genes is thought to be controlled epigenetically. Methods and Results: In this study, we set out to measure the effect of increased shelterin gene expression on telomere length in breast cancer cell line 21NT treated with 5-aza-2-deoxycytidine (5-aza-CdR) using known telomere length assays. We measured telomere lengths using: Telomere Restriction Fragment length (TRF), absolute quantitative-PCR and cytogenetic Interphase Quantitative Fluorescent in situ Hybridization (iQ-FISH). We found that non-cytotoxic levels of 5-aza-CdR affect telomere lengths by causing a significant and stable increase in telomere lengths of the breast cancer cell line. The increase in telomere lengths was consistently observed when various telomere length methods were used. Conclusions: Further investigation is required to understand the underlying mechanism involved, and the significance of telomere length elongation in relation to clinical outcome when epigenetic modifying drugs are utilized.
文摘端粒保护蛋白1(protection of telomeres 1,POT1)几乎存在于所有真核生物中,是一种高度保守表达的蛋白质,它与一系列相关的端粒结合蛋白共同参与保护端粒的结构和功能。随着近年来研究的深入,POT1与端粒的结合特点以及保护端粒的机制有了进一步的完善。此外,POT1对端粒长度的调节方式以及与肿瘤的发生、发展和细胞凋亡等关系也呈现出多样化。结合近几年的研究文献,对POT1的功能以及与其它相关蛋白的作用加以综述。
基金Acknowledgements This study was supported by the National Basic Research Program （973 Program） （Nos. 2012CB911201 and 2010CB945401）, the National Natural Science Foundation （Grant Nos. 31371508, 91019020 and 81330055）, the Introduced Innovative R and D Team of Guangdong Province （No. 201001Y0104687244）, Zhujiang Program of Science and Technology Nova in Guangzhou （No. 2011 J2200082）.
文摘Telomeres, the ends of linear eukaryotic chromosomes, are tandem DNA repeats and capped by various telomeric proteins. These nucleoprotein complexes protect telomeres from DNA damage response （DDR）, recombination, and end-to-end fusions, ensuring genome stability. The human telosome/shelterin complex is one of the best-studied telomere-associated protein complexes, made up of six core telomeric proteins TRF1, TRF2, TIN2, RAPI, POT1, and TPPI. TPP1, also known as adrenocortical dysplasia protein homolog （ACD）, is a putative mammalian homolog of TEBP-β and belongs to the oligonucleotide binding （OB）-fold-containing protein family. Three functional domains have been identified within TPP1, the N-terminal OB fold, the POT1 binding recruitment domain （RD）, and the carboxyl-terminal TIN2-interacting domain （TID）. TPP1 can interact with both POT1 and TIN2 to maintain telomere structure, and mediate telomerase recruitment for telomere elongation. These features have indicated TPP1 play an essential role in telomere maintenance. Here, we will review important findings that highlight the functional significance of TPP1, with a focus on its interaction with other telosome components and the telomerase. We will also discuss potential implications in disease therapies.
基金supported by National Natural Science Foundation of China(Grant Nos.81871109,31401223,81330055,31570827,91749113,91640119 and 31871479)National Key Research and Development Program of China(2017YFA0102801,2018YFA0107003)Natural Science Foundation of Guangdong Province(2017A030313116).
文摘Pluripotent stem cells(PSCs)such as embryonic stem cells(ESCs),ESCs derived by somatic cell nuclear transfer(ntESCs),and induced pluripotent stem cells(iPSCs)have unlimited capacity for self-renewal and pluripotency and can give rise to all types of somatic cells.In order to maintain their self-renewal and pluripotency,PSCs need to preserve their telomere length and homeostasis.In recent years,increasing studies have shown that telomere reprogramming is essential for stem cell pluripotency maintenance and its induced pluripotency process.Telomere-associated proteins are not only required for telomere maintenance in both stem cells,their extra-telomeric functions have also been found to be critical as well.Here,we will discuss how telomeres and telomere-associated factors participate and regulate the maintenance of stem cell pluripotency.
