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The Telomere Code - Biomatics.org

The Telomere Code

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A telomere is a region of repetitive DNA at the end of chromosomes, which protects the end of the chromosome from destruction. Its name is derived from the Greek nouns telos (τἐλος) "end" and merοs (μέρος, root: μερεσ-) "part".

During cell division, the enzymes that duplicate the chromosome and its DNA cannot continue their duplication all the way to the end of the chromosome. If cells divided without telomeres, they would lose the end of their chromosomes, and the necessary information it contains. (In 1972, James Watson named this phenomenon the "end replication problem".) The telomeres are disposable buffers blocking the ends of the chromosomes and are consumed during cell division and replenished by an enzyme, the telomerase reverse transcriptase.

Elizabeth Blackburn compared telomeres to the tips on the ends of shoelaces that keep them from unravelling.[1]

In 1975-1977, Blackburn, working as a postdoctoral fellow at Yale University with Joseph Gall, discovered the unusual nature of telomeres, with their simple repeated DNA sequences composing chromosome ends. Their work was published in 1978.

The telomerase shortening mechanism normally limits cells to a fixed number of divisions, and animal studies suggest that this is responsible for aging on the cellular level and sets a limit on lifespans. Telomeres protect a cell's chromosomes from fusing with each other or rearranging - abnormalities which can lead to cancer - and so cells are normally destroyed when their telomeres are consumed. Biologists speculate that this programmed death of potentially damaged cells reduces the likelihood of cancer but makes aging (and thus death) inevitable. Most cancers are the result of "immortal" cells which have ways of evading this programmed destruction.[2]

 

Contents

The Telomere as a Loop Counter?

In software engineering, a loop counter is the term often used to refer to the variable that controls the iterations of a loop (a computer programming language construct). It is so named because most uses of this construct result in the variable taking on a range of integer values in some orderly sequence (e.g., starting at 0 and end at 10 in increments of 1)

 

Loop counters change with each iteration of a loop, providing a unique value for each individual iteration. The loop counter is used to decide when the loop should terminate and for program flow to continue to the next instruction after the loop.

A common identifier naming convention is for the loop counter to use the variable names i, j and k (and so on if needed), where i would be the most outer loop, j the next inner loop, etc. The reverse order is also used by some programmers. This style is generally agreed to have originated from the early programming of FORTRAN, where these variable names beginning with these letters were implicitly declared as having an integer type, and so were obvious choices for loop counters that were only temporarily required. The practice also dates back further to mathematical notation where indices for sums and multiplications are often i, j, etc.





 

Telomere Quads G-quadruplexes like these are believed to form in the single-stranded region of telomeres. Telomerase is expressed selectively in cancer cells, and its activity is needed for them to proliferate. But it doesn't recognize its telomere substrates when they contain quadruplexes, so researchers believe drugs that form or stabilize quadruplexes might have anticancer activity.

hSnm1B Is a Novel Telomere-associated Protein

From the Department of Pharmacology and Cancer Biology, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710

Artemis, a member of the beta-CASP family, has been implicated in the regulation of both telomere stability and length. Prompted by this, we examined whether the other two putative DNA-binding members of this family, hSnm1A and hSnm1B, may associate with telomeres. hSnm1A was found to not interact with the telomere. Conversely, hSnm1B was found to associate with telomeres in vivo by both immunofluorescence and chromatin immunoprecipitation. Furthermore, the C terminus of hSnm1B was shown to interact with the TRF homology domain of TRF2 indicating that hSnm1B is likely recruited to the telomere via interaction with the double-stranded telomere-binding protein TRF2. 

Telomeric Protein Distributions and Remodeling Through the Cell Cycle in S. cerevisiae

Christopher D. Smith1, Dana L. Smith1, Joe L. DeRisi1, and Elizabeth H. Blackburn1* 1 University of California, Department of Biochemistry and Biophysics, 513 Parnassus Avenue, San Francisco, CA 94143-0448 * Corresponding author. E-mail address: telomer@itsa.ucsf.edu.

 In S. cerevisiae, telomeric DNA is protected by a non-nucleosomal protein complex, tethered by the protein Rap1. Rif and Sir proteins, which interact with Rap1p, are thought to have further interactions with conventional nucleosomic chromatin to create a repressive structure that protects the chromosome end. We showed by microarray analysis that Rif1p association with the chromosome ends extends to subtelomeric regions many kilobases internal to the terminal telomeric repeats and correlates strongly with the previously determined genomic footprints of Rap1p and the Sir2-4 proteins in these regions. While the end-protection function of telomeres is essential for genomic stability, telomeric DNA must also be copied by the conventional DNA replication machinery and replenished by telomerase, suggesting that transient remodeling of the telomeric chromatin might result in distinct protein complexes at different stages of the cell cycle. Using chromatin immunoprecipitation, we monitored the association of Rap1p, Rif1p, Rif2p, and the protein component of telomerase, Est2p, with telomeric DNA through the cell cycle. We provide evidence for dynamic remodeling of these components at telomeres. 

Genome stability and telomere maintenance

 

In the past few years, one major focus of our laboratory has been to elucidate the protein complexes that participate in regulating genome stability, particularly those involved in telomere end protection, maintenance, and signaling. Towards this end, we have been systematically analyzing protein networks that regulate human telomeres. During this process, we identified a novel telomere binding protein PTOP/TPP1 that interacts with telomeric proteins TIN2 and POT1, and participates in telomere regulation. Interestingly, we found that the TPP1 and POT1 acts as a heterodimer to bind to telomere DNA overhangs with higher affinity, and interacts directly with telomerase. We have also discovered that the six core telomere proteins (TRF1, TRF2, POT1, RAP1, TIN2, and TPP1) can form a high-order complex, the telosome. To date, we have purified more than 20 protein complexes related to telomere maintenance in human cancer cell lines. Analyses of these complexes have led us to propose the Telomere Interactome, an interaction network of telomere regulators in mammalian cells. Our analysis indicates that diverse types of enzymes and activities are present at the human telomeres. These activities and factors are recruited and assembled on the telomeres through the telosome platform and its sub-complexes. We are interested in the mechanisms by telomeric proteins regulate diverse signaling pathways.
http://www.bcm.edu/cmb/?pmid=2439

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