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First published online September 12, 2003
doi: 10.1242/10.1242/jcs.00765

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Hiding at the ends of yeast chromosomes: telomeres, nucleases and checkpoint pathways

School of Biological Sciences, University of Manchester, G38 Stopford Building, Oxford Road, Manchester M13 9PT, UK

View larger version (16K): [in a new window]   Fig. 1. Six classes of functional telomere in budding yeast. Natural telomeres of budding yeast are illustrated in A and B (Pryde and Louis, 1997) and other types of functional telomere are illustrated in C to F. The data and colouring scheme are from the website of Ed Louis (http://www.le.ac.uk/ge/ejl12/research/telostruc/EndsSmall.html). (A) Y' telomeres contain the three major repetitive sequences found at budding yeast telomeres: G-rich, Y' and X repeats. G-rich and X repeats are found at all telomeres. The G-rich repeats are the product of telomerase activity and are approximately 300 bp in wild-type budding yeast strains. X repeats are based on a 473 bp core sequence that contains an ARS (autonomously replicating sequence) consensus sequence, the binding site of the origin recognition complex and a separate Abf1 (ARS binding factor 1) binding site (Pryde and Louis, 1997; Pryde and Louis, 1999). Y' repeats are considerably larger than X repeats, with two predominant sizes of 5.2 and 6.7 kb (Lundblad and Blackburn, 1993). Y' repeats also contain ARS consensus sequences and Abf1 binding sites and are therefore potential origins of replication (Pryde and Louis, 1997). In addition, Y' repeats encode a functional helicase (Yamada et al., 1998). (B) X telomeres contain only G-rich and X repeats (C) In the absence of telomerase, or if telomere capping is defective, cells enter crisis and generate survivors. Type I survivors lose most of the G-rich repeats but amplify Y' repeats by recombination-dependent mechanisms. (D,E) In the absence of telomerase, Type II survivors contain highly lengthened G-rich repeats that have been maintained by recombination-dependent mechanisms. (F) If a DSB is induced close to a G-rich telomere seed sequence a telomere can be formed de novo.

View larger version (19K): [in a new window]   Fig. 2. Telomere replication. (A) Telomeres in all organisms contain a short 3' overhang on the G rich strand. (B) A replication fork moving towards the end of the chromosome. (C) The newly replicated, lagging C strand, will generate a natural 3' overhang when the RNA primer is removed from the final Okazaki fragment, or if the lagging strand replication machinery cannot reach the end of the chromosome. In the absence of nuclease activity the unreplicated 3' strand will be the same length as it was prior to replication. (D) The newly replicated leading G strand will be the same length as the parental 5' C strand, and blunt ended if the replication fork reaches the end of the chromosome. Therefore the newly replicated 3' G strand will be shorter than the parental 3' strand and unable to act as a substrate for telomerase because it does not contain a 3' overhang. If the leading strand replication fork does not reach the end of the chromosome a 5' rather than 3' overhang would be generated, but this would not be a suitable substrate for telomerase.

View larger version (23K): [in a new window]   Fig. 3. A spectrum of telomeric states. A model showing three states at budding yeast telomeres. (A) A fully capped telomere that prevents checkpoint activation and repair pathways. It is capped by numerous telomere-binding proteins, indicated by T. (B) An uncapped telomere that has recruited the PIKK kinase Tel1p, the checkpoint protein Rad9p, and the MRX complex (encoded by MRE11, RAD50 and XRS2). This type of telomere is a weak inhibitor of cell division based on the fact that the TEL1-dependent response to unresected DSBs is weak (Usui et al., 2001) and that Tel1p overexpression causes transient arrest (Viscardi et al., 2003). Tel1p appears to be a potent activator of telomerases and contributes to telomere capping. (C) A resected, DSB-like telomere that has recruited the core members of the DNA damage checkpoint response, including MEC1, MEC3, RAD9, RAD17 and DDC1. This DSB-like telomere is a potent activator of cell cycle arrest but less efficient at recruiting telomerase.