Telomerase- structure functions and activity regulation - bcm_1563.pdf

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Telomeres are DNA–protein structures that are localized at the ends of eukaryotic chromosomes. They protect the linear ends of eukaryotic chromosomes against degradation and fusion, thus maintaining genome stability. The cell replication apparatus is not able to pro- vide for complete replication of chromosome ends; also, telomeres are subject to the action of nucleases and other destructive factors. As a result, telomeres shorten during each cell division (Fig. 1). In most organisms the main mechanism of telomere length maintenance is comple- tion of DNA telomere repeats by telomerase [1]. This enzyme elongates the chromosome 3 -end, whereas the complementary strand is completed by DNA polymeras- es. Telomerase is a ribonucleoprotein complex [2]. The core enzyme includes telomerase reverse transcriptase and telomerase RNA containing a template site for DNA elongation. The telomerase complex also contains a num- ber of auxiliary components that provide for functioning of telomerase in vivo . Some of these components are nec- essary for telomerase attachment to the telomere at a cer- tain cell cycle phase [3], while others are required for reg- ulation of telomerase activity [4]. Some proteins are nec- essary for maturation of the telomerase complex and degradation of its components [5]. The amount of telom- erase in the different types of cells undergoes fine regula- tion [6, 7]. This is important because telomere shortening in human cells and finally senescence will result in restriction of cell division potential [8]. There are data showing that activation of telomerase is associated with the development of cancer [9], and that it is active in cells exhibiting potential for unlimited division. It is known that telomerase is active in 85% of cancer tumors, while in the other 15% of cases different mechanisms of telo- ISSN 0006-2979, Biochemistry (Moscow), 2010, Vol. 75, No. 13, pp. 1563-1583. © Pleiades Publishing, Ltd., 2010. Original Russian Text © M. I. Zvereva, D. M. Shcherbakova, O. A. Dontsova, 2010, published in Uspekhi Biologicheskoi Khimii, 2010, Vol. 50, pp. 155-202. REVIEW 1563 Abbreviations : CTE, C-terminal TERT domain (C-terminal extension); IFD, TERT domain (insertion in fingers domain); Pif1p, helicase of Saccharomyces cerevisiae ; TER, telomerase RNA; TERRA, RNA transcribed from telomeric DNA (telom- eric repeat-containing RNA); TERT, telomerase reverse tran- scriptase; TLC1 RNA, telomerase RNA of Saccharomyces cere- visiae ; TWJ, Y-like structural element of RNA (three way junc- tion). * To whom correspondence should be addressed. Telomerase: Structure, Functions, and Activity Regulation M. I. Zvereva*, D. M. Shcherbakova, and O. A. Dontsova Faculty of Chemistry, Lomonosov Moscow State University, 119999 Moscow, Russia; E-mail: [email protected] Received January 25, 2010 Revision received May 1, 2010 Abstract —Telomerase is the enzyme responsible for maintenance of the length of telomeres by addition of guanine-rich repetitive sequences. Telomerase activity is exhibited in gametes and stem and tumor cells. In human somatic cells prolifer- ation potential is strictly limited and senescence follows approximately 50-70 cell divisions. In most tumor cells, on the con-
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