Journal ArticleDOI
New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin.
Reads0
Chats0
TLDR
This work proposes a model in which two factors specifically target telomeres for the action of telomerase, as opposed to recombination or non-homologous end-joining, and proposes a potential protective role of amplified subtelomeric DNAs, which may aid capping of telomere capping maintained by non-telomerase based mechanisms through the formation of heterochromatin.Abstract:
Telomeres are stabilized, and telomeric DNA is replenished, by the action of the ribonucleoprotein reverse transcriptase telomerase. Telomere capping functions include the ability of telomeres to protect chromosome ends from cellular DNA-damage responses such as cell cycle arrest or apoptosis. This property of telomeres is especially important for cancer cells, which continue proliferating despite chromosome aberrations. Telomere capping is influenced by multiple, mutually reinforcing factors including telomere length, although telomere length is only one of several determinants of telomere functionality. For example, many cancer cells express high levels of telomerase yet maintain relatively short telomeres. We consider three aspects of telomere capping that have emerged relatively recently: (1) a new role for telomerase in telomere capping independent of its function in telomere elongation. Support for this novel function comes from experiments showing an increase in replicative potential with the reactivation of telomerase, without net telomere lengthening; (2) the role at telomeres of DNA damage proteins. We propose a model in which two factors specifically target telomeres for the action of telomerase, as opposed to recombination or non-homologous end-joining: binding by telomeric proteins that limits DNA damage responses at telomeres, and the affinity of the telomerase RNP for telomeric proteins and DNA; and (3) we discuss a potential protective role of amplified subtelomeric DNAs, which may aid capping of telomeres maintained by non-telomerase based mechanisms through the formation of heterochromatin.read more
Citations
More filters
Journal ArticleDOI
ATM and related protein kinases: safeguarding genome integrity
TL;DR: Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.
Journal ArticleDOI
Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II
TL;DR: It is reported that telomeric repeats are transcribed by DNA-dependent RNA polymerase II, which, in turn, interacts with the TRF1 shelterin protein, suggesting that TelRNAs may regulate telomerase activity at chromosome ends.
Journal ArticleDOI
Senescence and immortalization: role of telomeres and telomerase
Jerry W. Shay,Woodring E. Wright +1 more
TL;DR: It is argued that telomere shortening in the absence of other alterations may be a potent tumor suppressor mechanism and the evidence for and against the major molecular mechanisms proposed to initiate replicative senescence are discussed.
Journal ArticleDOI
Telomere length, stem cells and aging
TL;DR: The current evidence linking telomere shortening to aging and stem cell dysfunction is reviewed to suggest that telomerase activity and telomeres length can directly affect the ability of stem cells to regenerate tissues.
Journal ArticleDOI
The epigenetic regulation of mammalian telomeres
TL;DR: The links between epigenetic status and telomere-length regulation provide important new avenues for understanding processes such as cancer development and ageing, which are characterized by telomeres-length defects.
References
More filters
Journal ArticleDOI
Specific association of human telomerase activity with immortal cells and cancer
Nam Woo Kim,Mieczyslaw A. Piatyszek,Karen R. Prowse,Calvin B. Harley,Michael D. West,Peter L. C. Ho,Gina M. Coviello,Woodring E. Wright,Scott L. Weinrich,Jerry W. Shay +9 more
TL;DR: A highly sensitive assay for measuring telomerase activity was developed in this paper, which showed that telomerases appear to be stringently repressed in normal human somatic tissues but reactivated in cancer, where immortal cells are likely required to maintain tumor growth.
Journal ArticleDOI
Telomeres shorten during ageing of human fibroblasts.
TL;DR: The amount and length of telomeric DNA in human fibroblasts does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo.
Journal ArticleDOI
Identification of a specific telomere terminal transferase activity in tetrahymena extracts
TL;DR: It is proposed that the novel telomere terminal transferase is involved in the addition of telomeric repeats necessary for the replication of chromosome ends in eukaryotes.
Journal ArticleDOI
The DNA damage response: putting checkpoints in perspective
TL;DR: The inability to repair DNA damage properly in mammals leads to various disorders and enhanced rates of tumour development, and this work has shown that direct activation of DNA repair networks is needed to correct this problem.
Journal ArticleDOI
Mammalian Telomeres End in a Large Duplex Loop
Jack D. Griffith,Laurey Comeau,Soraya Rosenfield,Rachel M. Stansel,Alessandro Bianchi,Heidi Moss,Titia de Lange +6 more
TL;DR: Electron microscopy reported here demonstrated that TRF2 can remodel linear telomeric DNA into large duplex loops (t loops) in vitro, which may provide a general mechanism for the protection and replication of telomeres.