How does telomerase help in replication?
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In yeast cells, telomeres are replicated in late S phase in agreement with the late firing of subtelomeric origins. By contrast, in humans, subtelomeric origins might be activated earlier, although completion of replication is resumed very late because of delayed replication fork progression at the telomeric DNA repeats. Show
The unusual structures of telomeric chromatin hamper fork progression and may cause fork pause or arrest. We describe the events that allow the cell to alleviate these obstacles, pointing out the role of the telomeric DNA-binding proteins and of DNA-modifying enzymes. Formation of the telomere overhang is a key event in telomere replication and for telomerase recruitment and activity. We describe the different events that lead to telomerase-independent overhang formation. Overhang formation requires fork passage and the leading and the lagging strand may be processed in different ways. The erosion of telomeric DNA can be compensated for by elongation of telomeres by telomerase. We discuss the dynamic binding of telomerase and its associated proteins to telomeres during the cell cycle. AbstractThe replication of the ends of linear chromosomes, or telomeres, poses unique problems, which must be solved to maintain genome integrity and to allow cell division to occur. Here, we describe and compare the timing and specific mechanisms that are required to initiate, control and coordinate synthesis of the leading and lagging strands at telomeres in yeasts, ciliates and mammals. Overall, it emerges that telomere replication relies on a strong synergy between the conventional replication machinery, telomere protection systems, DNA-damage-response pathways and chromosomal organization. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution Relevant articlesOpen Access articles citing this article.
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Telomere repeat binding factor 2 interacts with base excision repair proteins and stimulates DNA synthesis by DNA polymerase β. Cancer Res. 66, 113–124 (2006). CAS PubMed Google Scholar Download references AcknowledgementsWe would like to thank M.-J. Giraud-Panis, T. Teixeira, A. Londono-Vallejo and P. Luciano for critical reading and helpful discussions. The E.G. and V.G. laboratories are supported by 'La Ligue Nationale contre le Cancer' ('Equipes labellisées'). We apologize for all the important papers that could not be cited due to space limitations. Author informationAuthors and Affiliations
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Ethics declarationsCompeting interestsThe authors declare no competing financial interests. Related linksRelated linksDATABASESEntrez Genome ProjectBorrelia burgdorferi FURTHER INFORMATIONEric Gilson's laboratory web site Vincent Géli's laboratory web site GlossaryCellular senescence A permanent form of cell-cycle arrest that can be induced by different types of exogenous or endogenous stress. Replicative senescence is triggered by an excessive telomere shortening that is the consequence of multiple rounds of cell division and is considered to be an intrinsic mechanism for limiting the proliferative lifespan of normal somatic cells. Reverse transcriptaseAn enzyme that copies single-stranded RNA into single-stranded DNA. ReplisomeA multiprotein complex at the junction of the DNA replication fork that contains all the enzymes that are required for DNA replication. PrimaseThe enzyme that synthesizes an RNA primer for initiation of DNA replication. Primase is associated with DNA polymerase-α to form a four-subunit complex. The polymerase-α–primase complex functions in the initiation of DNA replication at chromosomal origins and in the discontinuous synthesis of Okazaki fragments on the lagging strand of the replication fork. OB foldAn N-terminal oligonucleotide/oligosaccharide binding (OB) motif. The five-stranded β-sheet forms a closed β-barrel, which is capped by an α-helix located between the third and fourth strands. The OB fold is frequently used for the specific recognition of single-stranded nucleic acids. Origin recognition complexA heteromeric six-subunit protein complex that binds to DNA at replication origin sites and functions as a scaffold for the assembly of pre-replicative complexes in the G1 phase of the cell cycle. D-loopThe displacement loop structure that results from the displacement of a duplex DNA by a homologous single-stranded DNA. Position effectThe influence of the chromosomal context on various DNA transactions, including transcription, replication and recombination. It often refers to the repression that is conferred by heterochromatin proximity. Sir proteinsThe silent information regulators (Sir)-2, -3 and -4 are the structural constituents of a particular type of silent chromatin in budding yeast. At telomeres, Sir3 and Sir4 interact with the telomere-binding protein Rap1, can self-associate, and bind to deacetylated and demethylated N-terminal tails of histones H3 and H4 of subtelomeric nucleosomes. The deacetylase activity of Sir2 is required to spread the Sir complex along the chromatin toward the centromere. t-loopA structure adopted by telomeres that may result from invasion of the 3′ overhang into duplex DNA. G quadruplexA four-stranded structure that is held together by square planes of four guanines ('G-quartets'), associated through Hoogsteen base pairing. Once such structures form they are extremely stable and are likely to need enzymatic activity to be unwound in vivo. RecQ helicaseOne of a family of evolutionarily conserved helicases, mutations of which can lead to hereditary cancer-predisposition syndromes in humans. Helicases use the energy of ATP hydrolysis to unwind duplex DNA. DNA topoisomeraseAn enzyme that changes DNA supercoiling by inserting or removing superhelical twists. Rights and permissionsReprints and Permissions About this articleCite this articleGilson, E., Géli, V. How telomeres are replicated. Nat Rev Mol Cell Biol 8, 825–838 (2007). https://doi.org/10.1038/nrm2259 What is the role of telomerase in replication?Telomeres provide a mechanism for their replication by semiconservative DNA replication and length maintenance by telomerase. Through telomerase repression and induced telomere shortening, telomeres provide the means to regulate cellular life span.
How does telomerase solve the end replication problem?Telomerase is a reverse transcriptase that adds telomeric repeats to the 3′ ends of each chromosome (3). In doing so, telomerase makes up for the shortcomings of semiconservative DNA replication, which cannot complete the synthesis of chromosome ends.
What happens to telomeres during DNA replication?Telomeres act as caps that protect the internal regions of the chromosomes, and they're worn down a small amount in each round of DNA replication.
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