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What Happens at the End?

Replication fork –  http://en.wikipedia.org/wiki/Telomere.

Organisms with linear chromosomes have to solve the problem that DNA replication makes them shorter. This is due to the fact that DNA polymerase can only add bases to the terminal 3′-OH of a DNA chain. The DNA replication initiation complex uses RNA primers to provide the initial 3′-OH and to initiate “lagging” strand synthesis.  While one strand can be copied all the way to the end of a chromosome, the other, lagging strand, must be primed at short intervals in order to provide a 3′ OH group for DNA polymerase as the replication fork advances through a chromosome.  The problem at the end of a chromosome then is that the lagging strand has nothing for the primer to bind to. Without some kind of solution,  each replication cycle would result in a shorter chromosome.

Telomeres solve this problem. And, their molecules have cool structures.

My recent post on DNA structures inspired an entire group of students to ask questions and comment. Some wanted to know about additional kinds of DNA structures that occur in the natural world. Telomeres are one kind of example. They contain short segments of repeated DNA sequences and were first observed by Elizabeth Blackburn in 1975[1]. The repeated sequences can form quadraplex (4-chain) DNA structures, but the significance of their role in maintaining chromosome length was not understood until 1984 when the telomerase enzyme was discovered.

NMR solution structure of Tetrahymena telomeric repeats [2].

quadraplex

element coloring viewed head on

quadraplex

molecule coloring viewed head on

quadraplex

element coloring viewed from the side

quadraplex

molecule coloring viewed from the side

Telomerase is the enzyme that “lengthens” the ends of chromosomes to provide DNA sequences for priming the lagging strand during DNA synthesis and its discovery, by Blackburn along with Carol Greider and Jack Szostak, led to the Nobel Prize in Physiology or Medicine in 2009 [3].  The enzyme, a ribonucleoprotein complex, is actually a reverse transcriptase that contains an embedded RNA molecule that provides a template for synthesizing short stretches of DNA at the chromosome’s end.

NMR solution structure of the telomerase RNA from Medaka [4].

RNA

Space fill RNA with element coloring

RNA

RNA with residue coloring

Telomerase catalytic core with RNA [5]

telomerase

Telomerase with RNA, element coloring

telomerase

Telomerase with RNA, element coloring

1. Blackburn, E., & Gall, J. (1978). A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena Journal of Molecular Biology, 120 (1), 33-53 DOI: 10.1016/0022-2836(78)90294-2

2. PDB ID: 1YBN – Esmaili, N. (2005). i-motif solution structure and dynamics of the d(AACCCC) and d(CCCCAA) tetrahymena telomeric repeats Nucleic Acids Research, 33 (1), 213-224 DOI: 10.1093/nar/gki160

3. Blackburn, E. (2010). Telomeres and Telomerase: The Means to the End (Nobel Lecture) Angewandte Chemie International Edition, 49 (41), 7405-7421 DOI: 10.1002/anie.201002387

4. PDB ID: 2MHI – Kim, N., Zhang, Q., & Feigon, J. (2013). Structure and sequence elements of the CR4/5 domain of medaka telomerase RNA important for telomerase function Nucleic Acids Research, 42 (5), 3395-3408 DOI: 10.1093/nar/gkt1276

5. PDB ID: 2ERD – Singh, M., Wang, Z., Koo, B., Patel, A., Cascio, D., Collins, K., & Feigon, J. (2012). Structural Basis for Telomerase RNA Recognition and RNP Assembly by the Holoenzyme La Family Protein p65 Molecular Cell DOI: 10.1016/j.molcel.2012.05.018

The pictures were made with Molecule World on the iPad. If you want to see these structures for yourself, you can find Molecule World in the iTunes store.

Molecule World™ was developed with funding from the National Science Foundation (SBIR IIP 1315426).  Any opinions, findings, conclusions, or recommendations expressed on this website are those of the authors and do not necessarily represent the official views, opinions, or policy of the National Science Foundation.

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