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For vital telomere function.(5) Shelterin consists of six proteins, TRF1, TRF
For crucial telomere function.(five) Shelterin consists of six proteins, TRF1, TRF2, TIN2, Rap1, TPP1 and POT1 (Fig. 2). TRF1 and TRF2 directly bind ds telomere DNA, when POT1 binds ss telomere DNA. TRF1 negatively regulates telomerase-mediated telomere elongation, as evidenced by the fact that overexpression and knockdown of TRF1 resulted in telomere shortening and elongation, respectively.(six)Difficult Life at TelomeresVertebrate telomere DNA consists of double-stranded (ds) TTAGGG CCCTAA repeats. The 3-end of TTAGGG-repeat DNA (referred to as the G-strand) and the 5-end of CCCTAA-repeat DNA (referred to as the C-strand) are at the DNA termini (Fig. 1A). At the extreme end from the G-strand DNA can be a single-stranded extension, known as the G-tail. The length of human ss G-tail is roughly 5000 nt. The length on the ds telomere repeats is variable amongst unique species. Human cells typically show roughly from many kb to 20 kb. Notably, congenic mouse strains conventionally utilised in mouse genetics have bigger telomere DNAs spanning from 30 to over 100 kb.(three) This really should be taken into account when outcomes obtained from experiments making use of experimental mice are interCancer Sci | July 2013 | vol. 104 | no. 7 | 790The SV40 in vitro replication technique recapitulates traditional semi-conservative DNA replication. Working with this method, it was observed that the replication fork is frequently stalled at telomere repeat DNAs that were included within the template plasmid. Furthermore, it was suggested that the replication fork progressed slowly at telomeres in HeLa cells when TRF1 or TRF2 was overexpressed.(7) These final results suggested that TRF1 and or TRF2-bound telomere chromatin was a poor substrate for DNA replication. The link among telomere chromatin and DNA replication was underscored when it was discovered that ds telomere DNA-binding protein Taz1 is needed for efficient DNA replication at telomeres in fission yeast Schizosaccharomyces pombe.(eight,9) In line with these results, human TRF1 is essential for the effective semi-conservative replication of ds telomere DNA.(10) When TRF1 was conditionally deleted, cells failed to replicate telomere DNA efficiently, top towards the activation of ATR, a sensor kinase monitoring ssDNA generated by replication HMGB1/HMG-1 Protein web stalling. Recently, it was reported that Timeless, a protein that protects the replication fork, associates with TRF1 and TRF2, thereby facilitating in vitro telomere replication in Xenopus egg extracts.(11) It really is doable that the overexpressed TRF1 and TRF2 sequestered replication proteins, including Timeless, from the replication fork, leading to the inefficient replication at telomeres within the above described experiment.(7,12)Telomeres as a Fragile SiteWhen cells are exposed to mild replication stresses, such as therapy with aphidicolin, which inhibits DNA polymerases,1 To whom correspondence need to be addressed. E-mail: fishikawlif.kyoto-u.ac.jpdoi: ten.1111cas.12165 2013 Japanese Cancer Association(A)Hemoglobin subunit alpha/HBA1 Protein Purity & Documentation aTTAGGGrepeats CCCTAArepeats TRF1 TRFG-quartet G-tail5’TIN3’TPP1 POT3’TRFTRFbRapFig. 2. Vertebrate shelterin complex. TRF1 and TRF2 straight bind to ds telomere DNA. Pot1 bind to ss G-strand DNA (G-tail). TPP1, Rap1 and POT1 are recruited to telomeres by protein rotein interactions.cTIFd3′ 5′(B) aR N N H N O H O H N N NH N H N R N N H N N N N H O H O RbG G G G 3′ H G G G G G G G G G G G G 5’cG G G G 3′ G G G G 3′ G G G G 5′ G G G G 5’HN NFig. 1. (A) Schematic representation of how telomere DNA is replicated. [a] Vertebrate.