Article

The Ends Have Arrived

Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Cell (Impact Factor: 32.24). 12/2009; 139(6):1038-40. DOI: 10.1016/j.cell.2009.11.033
Source: PubMed

ABSTRACT

The 2009 Nobel Prize in Physiology or Medicine has been awarded to Elizabeth Blackburn, Carol Greider, and Jack Szostak for their contributions to our understanding of how the ends of eukaryotic chromosomes, telomeres, are replicated by a specialized reverse transcriptase, telomerase. I present a personal view of the telomere field, putting the contributions of these three Nobel laureates into historical context.

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    • "The telomerase ribonucleoprotein (RNP) enzyme synthesizes short DNA repeats onto linear eukaryotic chromosome termini to offset the progressive loss of telomeric DNA during replication, ensuring genome stability and cellular replicative capacity (Zakian 2009). The minimal telomerase enzyme necessary and sufficient for the reconstitution of telomerase activity is composed of the catalytic telomerase reverse transcriptase (TERT) and the telomerase RNA (TR) component that harbors a short template region for telomeric DNA synthesis (Podlevsky and Chen 2012). "
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    ABSTRACT: Telomerase is a ribonucleoprotein (RNP) enzyme that requires an integral telomerase RNA (TR) subunit, in addition to the catalytic telomerase reverse transcriptase (TERT), for enzymatic function. The secondary structures of TRs from the three major groups of species, ciliates, fungi, and vertebrates, have been studied extensively and demonstrate dramatic diversity. Herein, we report the first comprehensive secondary structure of TR from echinoderms-marine invertebrates closely related to vertebrates-determined by phylogenetic comparative analysis of 16 TR sequences from three separate echinoderm classes. Similar to vertebrate TR, echinoderm TR contains the highly conserved template/pseudoknot and H/ACA domains. However, echinoderm TR lacks the ancestral CR4/5 structural domain found throughout vertebrate and fungal TRs. Instead, echinoderm TR contains a distinct simple helical region, termed eCR4/5, that is functionally equivalent to the CR4/5 domain. The urchin and brittle star eCR4/5 domains bind specifically to their respective TERT proteins and stimulate telomerase activity. Distinct from vertebrate telomerase, the echinoderm TR template/pseudoknot domain with the TERT protein is sufficient to reconstitute significant telomerase activity. This gain-of-function of the echinoderm template/pseudoknot domain for conferring telomerase activity presumably facilitated the rapid structural evolution of the eCR4/5 domain throughout the echinoderm lineage. Additionally, echinoderm TR utilizes the template-adjacent P1.1 helix as a physical template boundary element to prevent nontelomeric DNA synthesis, a mechanism used by ciliate and fungal TRs. Thus, the chimeric and eccentric structural features of echinoderm TR provide unparalleled insights into the rapid evolution of telomerase RNP structure and function.
    No preview · Article · Nov 2015 · RNA
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    • "Telomerase is a unique reverse transcriptase (RT) essential for de novo synthesis of telomeric DNA repeats onto chromosomal termini to counter progressive telomere shortening resulting from incomplete end replication (Zakian, 2009). The renewal capacity of highly proliferative cells, such as germline and stem cells, relies on telomere length maintenance by telomerase to offset cellular and organismal aging. "
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    ABSTRACT: Telomerase synthesizes telomeric DNA repeats onto chromosome termini from an intrinsic RNA template. The processive synthesis of DNA repeats relies on a unique, yet poorly understood, mechanism whereby the telomerase RNA template translocates and realigns with the DNA primer after synthesizing each repeat. Here, we provide evidence that binding of the realigned RNA/DNA hybrid by the active site is an essential step for template translocation. Employing a template-free human telomerase system, we demonstrate that the telomerase active site directly binds to RNA/DNA hybrid substrates for DNA polymerization. In telomerase processivity mutants, the template-translocation efficiency correlates with the affinity for the RNA/DNA hybrid substrate. Furthermore, the active site is unoccupied during template translocation as a 5 bp extrinsic RNA/DNA hybrid effectively reduces the processivity of the template-containing telomerase. This suggests that strand separation and template realignment occur outside the active site, preceding the binding of realigned hybrid to the active site. Our results provide new insights into the ancient RNA/DNA hybrid binding ability of telomerase and its role in template translocation.
    Full-text · Article · Jan 2012 · The EMBO Journal
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    • "Since then, it has become apparent that several aspects of telomere biology are relevant to human cancer, offering potential opportunities for clinical intervention. In the work by Blackburn, Greider and Szostak, that was awarded the 2009 Nobel Prize in Physiology and Medicine (Zakian 2009), the structure of the chromosome ends was discovered to be specialized nucleoprotein structures that comprise the ''end zone " of chromosomes, called telomeres. "

    Full-text · Chapter · Oct 2011
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