telomere maintenance

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DESCRIPTION:

Telomeres, the specialized ends of eukaryotic chromosomes, are required for normal cell growth.
Telomere capping conceals and disguises the ends of chromosomal DNA so to distinguish it from double stranded DNA breaks. Telomere capping thereby prevents the fusion of chromosome ends, an event associated with genetic instability and a hallmark in the development of cancer. 
Telomere maintenance is essential for cancer growth. Induction of telomere dysfunction, for example, by inhibition of telomeric proteins or telomerase, has been shown to strongly enhance cancer cells’ sensitivity to chemotherapies.

Telomeres are at the extremities of chromosome DNA. The telomeric 3′ end terminates as a single-stranded, G-rich overhang able to form the t-loop, in which the overhang invades the telomeric double helix, remodeling the DNA into a circle. Telomeres are capped by at least 6 proteins (TRF1, TRF2, TPP1, POT1, TIN2, and Rap1), collectively known as shelterin, that physically shield the DNA. TRF1, TRF2, and TPP1 specifically recognize and bind to double-stranded TTAGGG repeats; POT1 binds to the single-stranded telomeric overhang; TIN2 and Rap1 complete the shelterin complex. Shelterin allows discrimination of telomeres from double-stranded DNA breaks; lack of shelterin allows telomeres to be identified as double-stranded DNA breaks and triggers DNA-damage pathways.

Genomic stability is maintained by telomeres, the end terminal structures that protect chromosomes from fusion or degradation. Shortening or loss of telomeric repeats or altered telomere chromatin structure is correlated with telomere dysfunction such as chromosome end-to-end associations that could lead to genomic instability and gene amplification. The structure at the end of telomeres is such that its DNA differs from DNA double strand breaks (DSBs) to avoid nonhomologous end-joining (NHEJ), which is accomplished by forming a unique higher order nucleoprotein structure. Telomeres are attached to the nuclear matrix and have a unique chromatin structure. Whether this special structure is maintained by specific chromatin changes is yet to be thoroughly investigated. Chromatin modifications implicated in transcriptional regulation are thought to be the result of a code on the histone proteins (histone code). This code, involving phosphorylation, acetylation, methylation, ubiquitylation, and sumoylation of histones, is believed to regulate chromatin accessibility either by disrupting chromatin contacts or by recruiting non-histone proteins to chromatin. The histone code in which distinct histone tail-protein interactions promote engagement may be the deciding factor for choosing specific DSB repair pathways. Recent evidence suggests that such mechanisms are involved in DNA damage detection and repair. Altered telomere chromatin structure has been linked to defective DNA damage response (DDR), and eukaryotic cells have evolved DDR mechanisms utilizing proficient DNA repair and cell cycle checkpoints in order to maintain genomic stability. Recent studies suggest that chromatin modifying factors play a critical role in the maintenance of genomic stability.

Over 90% of all tumours have (regained) telomerase activity.





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ORTHOLOGY CLASS Homo sapiens L. (human) [HSA] Mus musculus L. (mouse) [MMU] Caenorhabditis elegans Maupas (nematode) [CEL] Drosophila melanogaster Meigen (fruit fly) [DME] Saccharomyces cerevisiae Meyen ex E.C. Hansen (budding yeast) [SCE] Schizo-saccharomyces pombe Lindner (fission yeast) [SPO] Escherichia coli Migula (bacterium) K-12 MG1655 [ECO] Arabidopsis thaliana (L.) Heynh. (mouse-ear cress) [ATH]
ko:K11136 (regulator of telomere elongation helicase 1 [EC:3.6.4.12]) RTEL1 Rtel1 rtel-1 gi:24639946 gi:42563365
ko:K11133 (telomere replication protein) EST3
ko:K11132 (telomere elongation protein [EC:2.7.7.-]) EBS1
EST1
ko:K11127 (telomerase protein component 1) TEP1 Tep1
ko:K11126 (telomerase reverse transcriptase [EC:2.7.7.49]) TERT (telomerase catalytic subunit) Tert EST2 trt1 ATTERT
ko:K11125 (protein SMG5) SMG5 Smg5 Smg5
ko:K11124 (protein SMG6 [EC:3.1.-.-]) SMG6 Smg6 smg-6 Smg6
ko:K09426 (Myb-like DNA-binding protein RAP1) RAP1
ko:K11123 (regulatory protein SIR4) SIR4
ko:K11122 (regulatory protein SIR3) SIR3
ko:K11121 (NAD-dependent histone deacetylase SIR2 [EC:3.5.1.-]) SIR2
HST2
HST1
hst2
sir2
ko:K11120 (regulatory protein SIR1) SIR1
ko:K11119 (RAP1-interacting factor 2) RIF2
ko:K11118 (RAP1-interacting factor 1) RIF1
ko:K11117 (protein STN1) STN1
ko:K11116 (telomere length regulation protein) TEN1
ko:K11115 (cell division control protein 13) CDC13
ko:K11114 (adrenocortical dysplasia protein) ACD Acd
ko:K11113 (telomeric repeat-binding factor 2-interacting protein 1) TERF2IP Terf2ip
ko:K11112 (TERF1-interacting nuclear factor 2) TINF2 Tinf2
ko:K11111 (telomeric repeat-binding factor 2) TERF2 Terf2
ko:K11110 (telomeric repeat-binding factor 1) TERF1 Terf1
ko:K11109 (protection of telomeres protein 1) POT1 Pot1b
Pot1a
pot1

Last modification date: Oct. 18, 2011