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Introduction short telomeres [56,126,138–140]. More than its nuclease activity, the structural integrity of MRX is important for telomere length maintenance in cycling cells [141]. Only in cells arrested in G2/M, the nuclease activity of Mre11 is required for telomere addition, suggesting a cell cycle-specific role of MRX at telomeres [70]. MRX seems to have also an protective role at telomeres, as it inhibits generation of telomeric ssDNA in cells lacking Ku [131] and cdc13-1 mutant [142]. Mammalian MRN physically interacts with TRF2 and is recruited to normal telomeres [143]. Also in shelterin lacking cells, MRN is recruited to dysfunctional telomeres [144] and is required to remove the 3’ telomeric overhang to promote chromosome fusions. MRN is also required to protect newly replicated leading strand telomeres from NHEJ [145,146] (for a review see [147]). Yeast RPA is also involved in telomere length regulation. Rfa2p binds to telomeres and is enriched at telomeres in S phase. rfa2 mutant has short telomeres due to reduced recruitment of Est1p, but not of Est2p and Cdc13p, at telomeres [148]. Tel1 kinase is also involved in telomere maintenance. Like Ku, MRX and Tel1 are also involved in nuclear retention of TLC1 RNA [128]. Cells lacking TEL1 have short but stable telomeres due to reduced Est1p and Est2 recruitment at telomeres, possibly owing to defective nuclear retention of TLC1 RNA [140,149]. Like at DSBs, telomeric Tel1 binding is also dependent on Xrs2 and is required for the recruitment of telomerase at short telomeres thereby leading to a preferential elongation of short telomeres [150,151]. The kinase activity of Tel1 is important for its lengthening activity [152,153] and Tel1 mutants with increased kinase activity have longer telomeres [154], but precise knowledge on telomeric Tel1 target is lacking [155]. In fission yeast, Tel1 (ATM) and Rad3 (ATR) phosphorylate the telomere protein Ccq1 and promote Ccq1 interaction with Est1 for telomere maintenance [156,157]. Mec1 is also involved in telomere maintenance, as mec1 mutants have short telomeres [158] and cells lacking both TEL1 or MRX and MEC1 undergo telomere shortening and exhibit senescence phenotypes characteristic of cells lacking telomerase [139,158]. Cells lacking telomerase undergo Mrc1 dependent checkpoint activation [159,160]. In the survivors arising from telomerase lacking cells or in cells lacking yKu, Mec1 binding to telomeres increases [161]. Thus, In contrast to Tel1, Mec1 associates with short, 19
Introduction functionally compromised telomeres. Mec1, RPA, Mec3 and Rad24 are also involved in telomeric recombination in post senescence survivors [162]. Rif1 and Rif2 inhibit Tel1 recruitment at telomeres. Rif2 competes with Tel1 for binding to the C terminus of Xrs2 and in the absence of Tel1, Rap1 inhibits MRX association at telomeres [163]. In the absence of Rif2, Tel1 can bind equally well to short and wild type length telomeres [56]. Similarly, mammalian ATM is recruited to shelterin lacking dysfunctional telomeres [144]. In mammalian telomeres, TRF2 represses ATM, whereas POT1 prevents activation of ATR [164]. Although telomeres are bound by the checkpoint proteins, the checkpoint response is not activated and DNA repair/recombination processes such as NHEJ and HR are inhibited (for a review see, [165,166]). The transient telomeric ssDNA generated during replication is bound by Cdc13 and this binding has been proposed to inhibit RPA binding [167]. In fission yeast, the lack of essential epigenetic markers for checkpoint signal amplification and cell cycle arrest could be one of the mechanisms by which telomeres avoid complete checkpoint response [168]. In fact in mouse model, ATR suppresses telomere fragility and recombination [169]. In case of plants, ATR regulates DNA damage response by inhibiting chromosomal fusions and transcription of DNA repair genes and also by promoting programmed cell death in stem cells [170]. Chromatin dynamics and nuclear organization are important for gene regulation, DNA replication and also for the maintenance of genome stability. The nucleus contains spatially and functionally distinct subcompartments for specific purposes. Generally, chromatin near the nuclear envelop is transcriptionally inactive and late-replicating. However, recent evidences suggest that there might be exceptions because during stress response active genes are associated with nuclear pores [171]. In telomerase positive cells, budding yeast telomeres are normally clustered into 3–6 highly dynamic foci, which can fuse, disappear and reappear. The anchoring of the 32 telomeres takes place in a nonrandom manner, dependent upon the genomic size of the chromosome arm and other factors. 20
Page 1 and 2: UNIVERSITÀ DEGLI STUDI DI MILANO-B
Page 3 and 4: Contents
Page 5 and 6: Abstract
Page 7 and 8: Riassunto
Page 9 and 10: Introduction
Page 11 and 12: Introduction In Saccharomyces cerev
Page 13 and 14: Introduction Figure 3: A: Diagram s
Page 15 and 16: Introduction The Replication Protei
Page 17 and 18: Introduction Rap1 C terminal is ess
Page 19 and 20: Introduction and highest at G1 phas
Page 21 and 22: Introduction cleaves the RNA strand
Page 23 and 24: Introduction In the G1 cell cycle p
Page 25: Introduction impaired, and nuclease
Page 29 and 30: Introduction increasing the interac
Page 31 and 32: Introduction Similarly in fission y
Page 33 and 34: Introduction constitutive phosphory
Page 35 and 36: Shelterin-Like Proteins and Yku Inh
Page 37 and 38: Bonetti et. al., PLoS Genet. 2010 M
Page 65 and 66: Rif1 Supports the Function of the C
Page 67 and 68: Anbalagan et. al., PLoS Genet. 2011
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Anbalagan et. al., PLoS Genet. 2011
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References Anbalagan et. al., PLoS
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Discussion The DNA damage proteins
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Discussion An hypothesis for the sp
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Discussion Figure 14: Model, part 2
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Telomeric G4 Discussion Apart from
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References 1. Hayflick L (1965) The
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References that is required for tel
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References 51. Surovtseva YV, Churi
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References telomere elongation in S
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References 100. Walker JR, Corpina
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References 124. Gravel S, Larrivée
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References 147. Lamarche BJ, Orazio
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References 170. Boltz KA, Leehy K,
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References 194. Nimonkar AV, Ozsoy
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