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• W2063423712 abstract "A series of new techniques developed by Sfeir et al. (2005) have made it possible to analyze the sequence at the terminus of mammalian telomeres and have shown that the C strand is subject to a highly specific DNA processing step. A series of new techniques developed by Sfeir et al. (2005) have made it possible to analyze the sequence at the terminus of mammalian telomeres and have shown that the C strand is subject to a highly specific DNA processing step. Over the years there has been considerable debate concerning the type of DNA structure present at each end of a mammalian chromosome (Chai et al., 2005Chai W. Shay J.W. Wright W.E. Mol. Cell. Biol. 2005; 25: 2158-2168Crossref Scopus (53) Google Scholar, Makarov et al., 1997Makarov V.L. Hirose Y. Langmore J.P. Cell. 1997; 88: 657-666Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar, Wright et al., 1997Wright W.E. Tesmer V.M. Huffman K.E. Levene S.D. Shay J.W. Genes Dev. 1997; 11: 2801-2809Crossref PubMed Scopus (554) Google Scholar). Replication of the telomeric DNA by the conventional replication machinery is predicted to generate a 3′ overhang at one telomere and a blunt end at the other (Wei and Price, 2003Wei C. Price C.M. Cell. Mol. Life Sci. 2003; 60: 2283-2294Crossref Scopus (43) Google Scholar). The telomere replicated by lagging-strand synthesis will inevitably end up with a short 3′ overhang due to removal of the RNA primer from the terminal Okazaki fragment and a longer overhang if this last Okazaki fragment is initiated internal to the DNA terminus. In contrast, the telomere replicated by leading-strand synthesis would have a blunt end if the parental DNA is copied to the 3′ terminus. The terminal structure of mammalian chromosomes has proved difficult to characterize because of the low abundance of ends and the repetitive nature of the telomeric DNA. However, it is now clear that overhangs of 35–600 nt are present on the G-rich strands of both telomeres. Consequently, the leading-strand telomere must be subject to some form of DNA processing. It has also become apparent that the 3′ overhangs fulfill a number of important functions in the cell (de Lange, 2002de Lange T. Oncogene. 2002; 21: 532-540Crossref PubMed Google Scholar, Wei and Price, 2003Wei C. Price C.M. Cell. Mol. Life Sci. 2003; 60: 2283-2294Crossref Scopus (43) Google Scholar). First, they are required for extension of the telomeric DNA by telomerase. Second, they are essential for forming the chromatin caps that protect chromosome ends from degradation and end-to-end fusion. One type of chromatin cap, the t loop, is formed by the 3′ overhang tucking back into the duplex region of the telomeric DNA to form a lariat-like structure on the end of the chromosome. Since t loops are probably disrupted during DNA replication, the overhang is also thought to form an alternative cap structure where it interacts with the G strand binding protein POT1. Despite the importance of G strand overhangs, we know relatively little about the processing reactions by which they are generated. Moreover, until a recent study by the Wright/Shay lab (Sfeir et al., 2005Sfeir A.J. Chai W. Shay J.W. Wright W.E. Mol. Cell. 2005; 18: 131-138Abstract Full Text Full Text PDF Scopus (152) Google Scholar), the actual structure of the overhangs on mammalian chromosomes remained poorly defined. Techniques to examine overhang structure had been developed in model organisms that were genetically tractable (yeast, Wellinger et al., 1996Wellinger R.J. Ethier K. Labrecque P. Zakian V.A. Cell. 1996; 85: 423-433Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar) or had abundant telomeres (ciliates, Jacob et al., 2001Jacob N.K. Skopp R. Price C.M. EMBO J. 2001; 20: 4299-4308Crossref Scopus (46) Google Scholar). These revealed that the overhangs on leading-strand telomeres must be generated by degradation of the C strand rather than by telomerase extending the G strand, because overhangs are still formed at both telomeres in telomerase-deficient cells. Studies with Tetrahymena then showed that the G strand is also subject to a specific cleavage reaction so that the resulting overhangs are usually 14–20 nt in length and the ends of both the G- and C strands terminate at specific positions within the telomeric repeat (Jacob et al., 2003Jacob N.K. Kirk K.E. Price C.M. Mol. Cell. 2003; 11: 1021-1032Abstract Full Text Full Text PDF Scopus (53) Google Scholar). However, it was unclear whether mammalian chromosomes would be subject to analogous cleavage reactions, because the overhang and the overall telomeric tract are so much longer. The whole question of mammalian overhang structure has suddenly become tractable thanks to a series of novel and highly innovative techniques developed by the Wright/Shay lab. These researchers developed a new method for analyzing overhang length and have used it to show that G strand overhangs are maintained in senescent human primary cells (Chai et al., 2005Chai W. Shay J.W. Wright W.E. Mol. Cell. Biol. 2005; 25: 2158-2168Crossref Scopus (53) Google Scholar). Thus, replicative senescence cannot be triggered by general G overhang loss as had been suggested. This method is also likely to yield exciting information about differential processing at each chromosome end. The article by Sfeir et al., 2005Sfeir A.J. Chai W. Shay J.W. Wright W.E. Mol. Cell. 2005; 18: 131-138Abstract Full Text Full Text PDF Scopus (152) Google Scholar, in a recent issue of Molecular Cell, presents three new techniques to analyze G and C strand termini. The advance behind each of the new techniques lies in the combination of terminus-specific ligation reactions with PCR amplification. Each technique involves setting up ligation reactions between chromosomal DNA and adaptor oligonucleotides that end in different permutations of the G or C strand telomeric repeat (Figure 1). The adaptor oligonucleotides are positioned close to the terminus of the telomeric G or C strand by hybridization to either the G overhang or a C strand guide oligonucleotide, but only oligonucleotides with the correct permutation of the telomeric repeat will hybridize directly adjacent to the terminal nucleotide and, hence, be ligated to the chromosomal DNA. The ligation products are then amplified with a chromosome specific primer and/or primers directed against sequence tags on the adaptor oligonucleotides. Two different approaches to C strand analysis demonstrated that the majority (∼80%) of the C strands terminate with the same sequence; —CCAATC-5′. This is true for both leading- and lagging-strand telomeres. The finding is important because it indicates that the C strand is subject to a tightly regulated processing reaction that resects DNA to a defined position within the telomeric repeat. Moreover, whereas much of the overhang on the lagging strand may be generated as a result of incomplete replication, it also appears to be subject to the same final C strand processing step as the overhang on the leading-strand telomere. Interestingly, analysis of the G strand termini yielded a very different result. Unlike the C strands, the G strands ended at a variety of positions within the telomeric repeat, with 5′ —GGTTAG, 5′—GGTTA and 5′—GGTT occurring the most frequently. Thus, the terminus of the G strand is unlikely to be created by a specific processing step but is more likely to result from the leading-strand replication machinery copying the C strand either completely or to within 1–2 nt of the terminus. In telomerase expressing cells, the 5′ —GGTTAG termini become more common, suggesting that the 3′ end was now created by telomerase extending the DNA terminus to the end of its template RNA. The lack of G strand processing at human telomeres differs from the situation in ciliates and may well reflect differences in the specificity of mammalian and ciliate G overhang binding proteins and/or the ability to form t loops. However, the striking similarity between the C strand processing reactions in such diverse organisms suggests that that this is a highly conserved step in telomere replication. Although the identity of the processing nuclease(s) is still unknown, some clues have been gained from work with model organisms. Telomeres from Tetrahymena with an altered telomeric sequence are processed almost normally, which suggests that the nuclease(s) are not particularly sequence specific (Jacob et al., 2003Jacob N.K. Kirk K.E. Price C.M. Mol. Cell. 2003; 11: 1021-1032Abstract Full Text Full Text PDF Scopus (53) Google Scholar). The specificity of the processing reaction could instead result from binding of a protective protein (e.g., POT1) that then provides a cleavage boundary. In yeast, the DNA repair nucleases Exo1 and Mre11 have been implicated in telomere processing, because mutations in either protein cause defects in overhang structure. However, these defects only become severe when other telomere components are also defective, so it is unclear whether they represent the true processing nucleases. Identification of the C strand processing nuclease(s) is an important next step in understanding telomere maintenance because these factors may provide targets to promote telomere shortening in cancer cells or telomere elongation in presenescent cells (Sfeir et al., 2005Sfeir A.J. Chai W. Shay J.W. Wright W.E. Mol. Cell. 2005; 18: 131-138Abstract Full Text Full Text PDF Scopus (152) Google Scholar). The advances made by the Shay/Wright group will greatly facilitate the identification process." @default.
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• W2063423712 title "Engineering the End: DNA Processing at Human Telomeres" @default.
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• W2063423712 doi "https://doi.org/10.1016/j.molcel.2005.03.024" @default.
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