Replication telomere

At last, nucleolin might play a specific role in telomeric replication and maintenance, as suggested by two types of data. First, it binds telomeric repeat (TTAGGG)n in vitro (Ishikawa et al, 1993 Pollice et al, 2000), with a marked preference for the single-stranded form. Secondly, it interacts in vitro and in vivo with hTERT (Khurts et al, 2004), the protein catalytic component of human telom-erase. This interaction takes place both in the cytoplasm and in the nucleolus, where it could promote the assembly of hTERT with the RNA subunit hTERC. As a conclusion, many data regarding the involvement of nucleolin in DNA replication are indirect and an experimental demonstration through knockdown or knockout studies is still awaited. 

Agents that stabilize G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalyzed by telomerase or the telomerase-independent mechanism, and could therefore act as antitumor agents [26-30]. 

T. S. Lendvay, D. K. Morris, J. Sah, B. Balasubramanian, and V. Lundblad. Senescence mutants of Saccharomyces cerevisiae with a defect m telomere replication identify three additional EST genes. Genetics, 144 (4), 1399-1412, 1996. 

Shawn Ahmed and Jonathan Hodgkin, MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans. Nature, 403 (2000), 159-164. 

Telomere replication, (a) In replication of the lagging strand, short RNA primers are added (pink) and extended hy DNA polymerase. When the RNA primer at the 5 end of each strand is removed, there is no nucleotide sequence to read in the next round of DNA replication. The result is a gap (primer gap) at the 5 end of each strand (only one end of a chromosome is shown in this figure), (h) Asterisks indicate sequences at the 3 end that cannot he copied hy conventional DNA replication. Synthesis of telomeric DNA hy telomerase extends the 5 ends of DNA strands, allowing the strands to he copied hy normal DNA replication. 

Boerckel J, Walker D, Ahmed S. The Caenorhabditis elegans Rad 17 homolog HRP-17 is required for telomere replication. Genetics. 2007 176 703-9. 

ITowever, most normal somatic cells lack telomerase. Consequently, upon every cycle of cell division when the cell replicates its DNA, about 50-nucleotide portions are lost from the end of each telomere. Thus, over time, the telomeres of somatic cells in animals become shorter and shorter, eventually leading to chromosome instability and cell death. This phenomenon has led some scientists to espouse a telomere theory of aging that implicates telomere shortening as the principal factor in cell, tissue, and even organism aging. Interestingly, cancer cells appear immortal because they continue to reproduce indefinitely. A survey of 20 different tumor types by Geron Corporation of Menlo Park, California, revealed that all contained telomerase activity. 

Since all DNA polymerases require a primer and work only in the 5 to 3 direction, there s a problem with replicating the 5 ends of the DNA. If an RNA primer has to be laid down and later removed, these ends can t get replicated. For bacteria with a circular genome, this isn t a problem. Eukaryotes have specialized structures called telomeres at the... 

Telomeres are r etitive sequences at the ends of linear DNA molecules in eukaryotic chromosomes. With each round of replication in most normal cells, the telomeres are shortened because DNA polymerase cannot complete synthesis of the 5 end of each strand. This contributes to the aging of cells, because eventually the telomeres become so short that the chromosomes cannot function properly and the cells die. 

Telomerase is an enzyme in eukaryotes used to maintain the telomeres. It contains a short RNA template complementary to the DNA telomere sequence, as well as telomerase reverse transcriptase activity (hTRT). Telomerase is thus able to replace telomere sequences that would otherwise be lost during replication. Normally telomerase activity is present only in embryonic cells, germ (reproductive) cells, and stem cells, but not in somatic cells. 

In summary, it will need to be demonstrated whether accelerated telomere shortening indeed represent the chronic phase clock reflecting both increased replicative aging of Ph-r HSC due to increased cell cycle activity as well as... 

Telomeres are seqnences of six-nucleotide repeats found at the ends of the chromosomal DNA strands. Many thon-sands of repeat nnits (TTAGGG) may be present at the end of the 3 strand and (AATCCC) at the end of the 5 strand. These are present at the ends of the strands to overcome a problem posed by the semi-conservative mechanism of DNA replication, known as the end replication problem . Replication of the ends of the chromosomes presents par-ticnlar difficnlties, since DNA polymerase can only elon-... 

Research work with large genomes and the associated need for high-capacity cloning vectors led to the development of yeast artificial chromosomes (YACS Fig. 9-8). YAC vectors contain all the elements needed to maintain a eukaryotic chromosome in the yeast nucleus a yeast origin of replication, two selectable markers, and specialized sequences (derived from the telomeres and centromere, regions of the chromosome discussed in Chapter 24) needed for stability and... 

Artificial chromosomes (Chapter 9) have been constructed as a means of better understanding the functional significance of many structural features of eukaryotic chromosomes. A reasonably stable artificial linear chromosome requires only three components a centromere, telomeres at each end, and sequences that allow the initiation of DNA replication. Yeast artificial chromosomes (YACs see Fig. 9-8) have been developed as a research tool in biotechnology. Similarly, human artificial chromosomes (HACs) are being developed for the treatment of genetic diseases by somatic gene therapy. 

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