Telomeric End-Binding Proteins

The cocrystal structures cited above provided no evidence of G-quartets or G4 DNA formed within the G-rich telomeric DNA complexed to the protein. While a higher resolution structure (1.86 A) of the Oxytricha telomere endbinding complex identified G-quartets stabilizing antiparallel interactions 

2 POTl Disrupts G-Quadruplexes to Promote Telomere Extension by Telomerase 

Why was G4 DNA not apparent in the cocrystals of telomeric DNA with ciliate TEBP complexes An explanation for this apparent paradox was provided by mutational analysis of TEBP (3, which showed that the basic C-terminal region of TEBPp is necessary to promote G4 DNA formation. Following the common divide and conquer strategy for structural analysis, this region had been truncated in the TEBPa/(3 heterodimer analyzed in the cocrystals.  

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Baumann, P., and Cech, T.R. (2001). Poll, the putative telomere end-binding protein in fission yeast and humans. Science 292, 1171-1175. 

K. Paeschke, T. Simonsson, J. Postberg, D. Rhodes and H.J. Lipps, Telomere end-binding proteins control the formation of G-quadruplex DNA structures in vivo, Nat. Struct. Mol. Biol., 2005, 12, 847-854. 

The X-ray crystal structure at 1.86 A resolution of the Oxytricha nova telomere end binding protein (OnTEBP) in complex with DNA and in the presence of NaCl (PDB ID 1JB7) has also shown that d(G4T4G4) adopts a... 

Three classes of proteins in addition to TERT are now known to be associated with various telomerases. Estlp was first found in yeast [21] it is essential for activity in vivo, but seems entirely dispensable for enzyme activity per se as judged by in vitro assays. Estlp interacts directly with the yeast telomere DNA end binding protein, Cdcl3p [22] this interaction appears to recruit telomerase to the chromosome end... 

Figure 5 Interactions of end-binding proteins with telomeric G-rich overhangs. (A) Human POTl binding disrupts G-quadruplexes to allow extension by telomer-ase at the 3 end of a telomeric overhang. (B) The ciliate end-binding complex TEBPajfi promotes G-quadruplex formation to prevent telomere extension...

As described before, an altered telomere state may be a more important consequence than critical telomere shortening (33). Thus, disruption of telesomes by either depletion of proteins involved in telomere binding (e.g., telomerase) or sequestration of telomere ends by stabilization of G-quadruplex structures, or both, may lead to chromosome end-to-end fusion in piesenescence cells. In fact, TMPyP4 and the fluoroquinophenoxazines have both been demonstrated to produce anaphase bridges, a hallmark of chromosome end fusions, in relatively short periods of time (78). 

S. cerevisiae felomers have 350 base pairs confaining fhe sequences (TGj 3 / C 3A) as well as one or more copies of a 6.7-kb nonrepefihve sequence and ofher elemenfs. In many species fhe repehfive felo-meric sequences have 3 poly(G) fails at the ends of fhe DNA molecules. These fails are able to form G quarfef sfrucfures (Fig. 5-26 and Chapter 5, Sechon C,4). A variety of telomere-binding proteins have been isolated. " Some of fhese bind to G quartet struc-... 

The two subunits of the Ku heterodimer comprise the second class of telomerase proteins. Ku is responsible for nonhomolo-gous end-joining of broken chromosomes, and initially it appeared odd or perhaps even dangerous that it would be telomere associated after all, telomeres protect chromosome ends from fusion events that result in genomic instabihty. A solution to this conundrum was recently provided by SteUwagen et al. [26], who showed that Ku binds directly to telomerase RNA and promotes the de novo addition of telomeres to broken chromosome ends, thereby helping... 

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