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Replication and protection of telomeres. Nature

The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037-1099, USA.
Nature (Impact Factor: 42.35). 07/2007; 447(7147):924-31. DOI: 10.1038/nature05976
Source: PubMed

ABSTRACT During the evolution of linear genomes, it became essential to protect the natural chromosome ends to prevent triggering of the DNA-damage repair machinery and enzymatic attack. Telomeres - tightly regulated complexes consisting of repetitive G-rich DNA and specialized proteins - accomplish this task. Telomeres not only conceal linear chromosome ends from detection and inappropriate repair but also provide a buffer to counteract replication-associated shortening. Lessons from many model organisms have taught us about the complications of maintaining these specialized structures. Here, we discuss how telomeres interact and cooperate with the DNA replication and DNA-damage repair machineries.

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Available from: Ramiro E Verdún, Mar 03, 2014
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    • "It is now well known that telomere-dependent senescence is induced by a change in the protected status of shortened telomeres, whereby the loss of telomere DNA contributes to this change [16]. The loss of telomere protection or any other cause of telomere dysfunction results in inappropriate chromosomal end-to-end fusions through non-homologous end joining or homologous recombination DNA repair pathways [17]. These DNA repair pathways are used principally to repair double-strand DNA breaks (DSBs). "
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    • ". Human telomeres. Top: Shelterin proteins, including TRF1, TRF2, TIN2, RAP1, TPP1, and POT1, interact with many proteins involved in cell cycle progression and DNA repair [14]. The telomerase complex is regulated by shelterin proteins and DNA structures at telomeres, such as T-loop and G-quadruplexes. "
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    ABSTRACT: Telomeres play important roles in maintaining the stability of linear chromosomes. Telomere maintenance involves dynamic actions of multiple proteins interacting with long repetitive sequences and complex dynamic DNA structures, such as G-quadruplexes, T-loops and t-circles. Given the heterogeneity and complexity of telomeres, single-molecule approaches are essential to fully understand the structure–function relationships that govern telomere maintenance. In this review, we present a brief overview of the principles of single-molecule imaging and manipulation techniques. We then highlight results obtained from applying these single-molecule techniques for studying structure, dynamics and functions of G-quadruplexes, telomerase, and shelterin proteins.
    DNA repair 08/2014; 20. DOI:10.1016/j.dnarep.2014.01.012 · 3.36 Impact Factor
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    • "Mammalian telomeres form a higher order structure by sequestering the ss-terminus into the double-stranded (ds) telomere DNA—thus forming a T-loop and protecting the chromosome terminus (7). Further, the highly repetitive G-rich sequences on the lagging strand can adopt unusual secondary structures, such as G-quadruplexes (G4-DNA) (8). Such alternate or secondary structures must be resolved prior to DNA replication. "
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    ABSTRACT: A variety of human tumors employ alternative and recombination-mediated lengthening for telomere maintenance (ALT). Human RecQ helicases, such as BLM and WRN, can efficiently unwind alternate/secondary structures during telomere replication and/or recombination. Here, we report a novel role for RECQL1, the most abundant human RecQ helicase but functionally least studied, in telomere maintenance. RECQL1 associates with telomeres in ALT cells and actively resolves telomeric D-loops and Holliday junction substrates. RECQL1 physically and functionally interacts with telomere repeat-binding factor 2 that in turn regulates its helicase activity on telomeric substrates. The telomeric single-stranded binding protein, protection of telomeres 1 efficiently stimulates RECQL1 on telomeric substrates containing thymine glycol, a replicative blocking lesion. Loss of RECQL1 results in dysfunctional telomeres, telomere loss and telomere shortening, elevation of telomere sister-chromatid exchanges and increased aphidicolin-induced telomere fragility, indicating a role for RECQL1 in telomere maintenance. Further, our results indicate that RECQL1 may participate in the same pathway as WRN, probably in telomere replication.
    Nucleic Acids Research 03/2014; 42(9). DOI:10.1093/nar/gku200 · 9.11 Impact Factor
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