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Lecture 3

Lecture 3 - The Eukaryotic Chromosome

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Biology 2581B
Jim Karagiannis

LECTURE 2: THE EUKARYOTIC CHROMOSOME Key Concepts 1. Flexibility in DNAstructure and organization 2. DNAtopology 3. Higher order chromosome structure 4. The unineme hypothesis AnAppreciation Scale • Double helix is 2 nm in width, however, if you were to stretch out an entire chromosome, it would be on the order of centimeters in length – about 2 m in length • Must be packaged within nucleus, which on the order of 10,000 nm – thus, has to be compacted • Must happen for every cell that makes up the body • Even though we are working at a tiny scale, changes at this scale have profound effects on our body Flexibility in DNAStructure • B-DNArepresents only one possible conformation that a DNAdouble helix can form • B form – right-handed helix – backbone spirals away to the right hand side • Z form – left-handed helix – backbone spirals away to the left hand side – backbone is not as smooth as in the B-DNA (minor groove is much smaller and major groove is much bigger in Z form) • Other forms of DNAalso exist. However, they do not form under physiological conditions and are thus not biologically relevant Biological Function of Z-DNA • The biological role of Z-DNAremains mysterious, but some evidence suggests that Z-DNAmay have a functional role within cells: o Z-DNAis formed transiently in association with transcription o Several viral proteins identified with highly specific Z-DNAbinding activities  e.g. Vaccinia virus E3Lprotein: essential for virulence o Antibodies to Z-DNAbind transcriptionally active regions Flexibility in Helical Structure • Acrucial property of the double helix is its ability to separate the two strands without disrupting covalent bonds. This makes it possible for the strands to separate and reform under physiological conditions. • This is important for the processes of DNAreplication, transcription, and also for DNArepair mechanisms. • Base flipping o Biological function of base flipping: enzymes involving DNArepair may scan for DNAlesions by flipping out bases Flexibility in DNAOrganization • Humans have DNAin the form of chromosomes, which are linear double- stranded molecules • Prokaryotic bacteria – circular, double-stranded molecules • Viruses – various conformations – both linear or circular, and single- stranded or double-stranded genomes Flexibility in DNATopology • Topology – refers to 3D arrangement of molecule in space – from a physics perspective • DNAmolecules can be classified into two groups topologically – those with topological constraint and those without • No constraint – linear molecule, where hydrogen bonds are broken down the entire length of double helix, you would be able to pull apart the two strands physically (two separate molecules) • With constraint – circular molecule, you would not be able to do this even if hydrogen bonds are broken – they are interwoven like links of a chain, and you would not be able to pull two strands apart • Constraints can occur in linear molecules as well – proteins at ends, causes strands to stick together, thus not allowing them to be separated • For a constrained double helix, torsional stress introduces supercoiling • Supercoiling results from both overwinding and underwinding • Overwound: o (+) writhe  (+) supercoiling / (+) superhelicity  (+) supercoiled DNA o Positive writhe introduces positive supercoiling/superhelicity which results in positively supercoiled DNA • Underwound: o (-) writhe  (-) supercoiling / (-) superhelicity  (-) supercoiled DNA o Negative writhe introduces negative supercoiling/superhelicity which results in negatively supercoiled DNA • Circular double-stranded molecule – as more negative superhelical energy is added, there is more supercoiling and the molecule becomes more and more compact DNASupercoiling • Relaxed DNAhas about 10.5 bp/turn of the double helix • Thus, for a DNAfragment 260 bp long, the two DNAstrands would cross each other 25 times. This is referred to as the linking number (i.e. Lk = 25) • Supercoiling can be induced if the DNAmolecule is underwound before the circle is made. • This destabilizes the helix (260 bp/23 turns= 11.3 bp/turn) • There are now two ways to stabilize the DNAmolecule: 1) partially separate the strands, or 2) introduce supercoils. • Living cells store their DNAwith negative superhelicity. Why? There are many instances when it is advantageous to drive the unwinding of the double helix. • For example, the stored energy could aid in processes that require strand separation (e.g. DNA replication, transcription) • Negative supercoiling is also useful in making the DNAmolecule more compact in prokaryotes o For example, the genome of E. coli exists as 4.5 Mb long closed, ds DNAcircle o Length of molecule = 1.6 mm o Length of E. coli = about 1.5
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