DNA STRUCTURE ANALYSIS

deoxyribonucleic acid : the nucleic acid in which the sugar is deoxyribose, constituting the primary genetic material of all cellular organisms and the DNA viruses, and occurring predominantly in the nucleus. It is a linear or circular polymer with a backbone composed of deoxyribose moieties that are linked by phosphate groups attached to their 5' and 3' hydroxyls, with side chains composed of purine (adenine, guanine) and pyrimidine (cytosine, thymine) bases attached to the sugars. The strands are twisted to form a double helix and are antiparallel. DNA is duplicated by replication, and it serves as a template for synthesis of ribonucleic acid (transcription).



Maurice Wilkins's research provided the proof that James Watson and Francis Crick needed to back up their theory about DNA's structure, which is the cornerstone to understanding how the molecule replicates and transfers its informationref. He pioneered a technique called X-ray fibre diffraction, which can reveal the molecular structure of biological material such as collagen or DNA. Previously, X-ray images could only be derived from crystals, which excluded many large biological molecules that prefer to form strands. Wilkins worked on the DNA project with Rosalind Franklin, who took the X-ray photograph that gave Watson and Crick their eureka moment. He then spent almost 10 years rigorously verifying that breakthrough.
linking number : in topology, the total number of times one strand of the DNA double helix winds around the other in a right hand direction, given a DNA molecule with constrained ends. 2 molecules differing only in linking number are topoisomers.
writhing number (W) : in topology, the number of superhelical turns in a DNA molecule with constrained ends Modern DNA polymerases can polymerize even threonucleotides to form a DNA-threonucleic acid (TNA) hybrid molecule with excellent base-pairing properties

Chromatin : the more readily stainable portion of the cell nucleus, forming a network of nuclear fibrils. It is a deoxyribonucleic acid attached to a protein (primarily histone) structure base and is the carrier of the genes in inheritance. It occurs in 2 states, euchromatin and heterochromatin, with different staining properties, and during cell division it coils and folds to form the metaphase chromosomes. the basic element of chromatin structure is the mononucleosome, an octamer of histones (2 copies each of

with 146 bp of DNA wrapped nearly twice around. Adjacent nucleosomes are separated by between 20 and 60 nt of DNA referred to as linker or internucleosomal DNA. A fifth histone, H1 ...: ..., binds to DNA as it exits the nucleosome and interacts with the linker DNA. H1 is thought to be essential for the condensation of polynucleosomes into higher order structures. These structures include a solenoid of helically arrayed nucleosomes and then some superhelical twisting of solenoidal loops, the bases of which are attached to a non-histone protein scaffold. Although high resolution X-ray crystallographic data exists that confirm the precise structure of the mononucleosome and its associated DNA, higher order structures are inferred from electronic microscopic observations and various indirect biochemical assays. Individual histones undergo posttranslational modification by phosphorylation, methylation and acetylation in ways that are expected to alter the local properties of chromatin structure, enhancing or inhibiting access of proteins to specific DNA sequences. These modifications are targeted by sequence-specific DNA-binding proteins (often transcription factors), which recruit modifying enzymes through protein-protein interactions. Finally, the positions of individual nucleosomes need not be static - they might be able to slide along the DNA, transiently exposing different sequences in the linker regions between thought to increase this sliding and thereby promote accessibility. DNA wrapped in nucleosomes is sterically occluded, creating obstacles for polymerase, regulatory, remodeling, repair and recombination complexes, which require access to the wrapped DNAref


(reproduced with permission from Nature Reviews Immunology (Vol 3, No. 11, pp 890-899(2003)) copyright Macmillan Magazines Ltd)

Histone modification map :
Design of enzymes that work with artificial bases : Stretches of transiently existing Z-DNA, of which there are perhaps 100,000 in the human genome, may help to switch on genes by making them more accessible to proteins, such as transcription factors, that stimulate gene activity. The vaccinia virus may specifically hijack vulnerable Z-DNA, thereby crippling human cells.

The number of replication origin sequences in the genome does not change during the lifespan of an organism, but the number of active origins does vary according to the developmental stage. In the early embryo, the greater number of active origins may be supported by the higher density of origin recognition proteins and by the less constrained genomic regulation. In later stages, more concerned with differentiation than proliferation, it is thought that epigenetic marking restrains most potential origins and restricts the speed of DNA replication and cell division, with the rate of replication fork movement remaining more or less constant : the efficiency of some origins relies more on nucleotide availability and/or fork progression rate than on specific cis-sequences. Some initiation sites identified lie in intergenic regions and co-map with previously identified A+T rich matrix attachment regions (MARs)ref.

Telomeres undergo 100 bp shortening at each replication cycle : when they become 3,000-5,000 bp-long, no further replication cycle can occur : telomeres can be artificially extended by using nanocircles which can stick to the consensus sequence. Mice have much longer telomeres than humans and do not normally undergo significant telomere shortening (which occurs in premalignant cells and aging tissues in humans) and crisis. However, engineered mice that do not possess mTerc (the RNA subunit of telomerase) display more gross chromosomal aberrations and have a shift in tumour spectrum to one that resembles that of aged humans. Mutations in the telomerase RNA component (TERC) cause autosomal dominant dyskeratosis congenita.

Silencing

Journals : Nucleic Acids Research [free at PubMedCentral : archive starts with Vol. 28(1); 2000]
Web resources :



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