dna e. mcintyre ib biology hl. dna is the genetic material therefore it must replicate faithfully....
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DNA
E. McIntyre
IB Biology HL
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DNA is the Genetic Material
• Therefore it must
• Replicate faithfully.
• Have the coding capacity to generate proteins and other products for all cellular functions.
“A genetic material must carry out two jobs: duplicate itself and control the
development of the rest of the cell in a specific way.”-Francis Crick
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Watson & Crick in action
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Models for DNA replication1) Semiconservative model:
Daughter DNA molecules contain one parental strand and one newly
replicated strand.
2) Conservative model:
Parent strands transfer information to an intermediate, then the
intermediate gets copied. The parent helix is conserved, the daughter
helix is completely new.
3) Dispersive model:
Parent helix is broken into fragments, dispersed, copied then
assembled into two new helices. New and old DNA are completely
Dispersed.
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(a) Hypothesis 1:
Semi-conservative replication
(b) Hypothesis 2:Conservative replication
Intermediate molecule
(c) Hypothesis 3:Dispersive replication
MODELS OF DNA REPLICATION
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Meselson and Stahl Semi-conservative replication of DNA
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The families of nitrogenous bases
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DNA Replication
• Since DNA replication is semiconservative, therefore the helix must be unwound.
• John Cairns (1963) showed that initial unwinding is localized to a region of the bacterial circular genome, called an “origin” or “ori” for short.
• DNA replication is semiconservative. Each strand of both replication forks is being copied.
• DNA replication is bidirectional. Bidirectional replication involves two replication forks, which move in opposite directions
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Evidence points to bidirectional replication
Label at both replication forks
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The Enzymes of Replication
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A 3’ hydroxylgroup is necessaryfor addition of nucleotides
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DNA Polymerase contains a Proofreading subunit
Accuracy of DNA polymerases is essential.
-Error rate is less than 1 in 108
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Proofreading by DNA polymerase
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DNA Exonuclease
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DNA replication is semi-discontinuous
Continuous synthesis
Discontinuous synthesis
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Proteins & the Replication Fork
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Protein complexes of the replication fork:
DNA polymerase
DNA primase
DNA Helicase
ssDNA binding protein
Sliding Clamp
Clamp Loader
DNA Ligase
DNA Topoisomerase
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DNA primasesynthesizes anRNA primerto initiate DNAsynthesis on thelagging strand
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Replication of the Lagging Strand
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DNA ligase seals nicks left by lagging strand replication
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DNA helicase unwinds the DNA duplex ahead of DNA polymerase creating single stranded DNA that can be used as a template
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DNA helicase moves along one strand of the DNA
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ssDNA binding proteins are required to “iron out” the unwound DNA
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ssDNA binding proteins bind to the sugar phosphate backboneleaving the bases exposed for DNA polymerase
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DNA polymerase is not very processive (ie it falls off the DNA easily). A “slidingclamp” is required to keep DNA polymerase on andallow duplication of longstretches of DNA
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A “clamp loader:” complex is required to get the clamp ontothe DNA
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Lagging strand synthesis
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The supercoiling ahead of the fork needs to be relieved or tension wouldbuild up (like coiling as spring) and block fork progression.
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Type I topoisomerases:Make nicks in one DNA strandsCan relieve supercoiling
Type II topoisomersases:Make nicks in both DNA strands (double strand break)Can relieve supercoiling and untangle linked DNA helices
Both types of enzyme form covalent intermediates with the DNA
Supercoiling is relieved by the action of Topoisomerases
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Topoisomerase I Action
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Topoisomerase II Action
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Topoisomerase II Action
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Because dividing cells require greater topoisomerase activitydue to increased DNA synthesis, topoisomerase inhibitors are used as chemotherapeutic agents.
e.g. Camptothecin -- Topo I inhibitor Doxorubicin -- Topo II inhibitor
These drugs act by stablilzing the DNA-Topoisomerase complex.
Also, some antibiotics are inhibitors of the bacterial-specific toposisomerase DNA gyrase
e.g. ciprofloxacin
Topoisomerases as drug targets
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DNA is replicated during S phase of the Cell Cycle
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In S phase, DNA replication begins at origins of replication that are spread out across the chromosome
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Each origin of replicaton initiates the formation of bidirectionalreplication forks
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Errors lead to over replication of specific chromosomal regions.
(= gene amplification)
This seen commonly in cancer cells and can be an importantprognostic indicator.
It can also contribute to acquired drug resistance.
Origins of replication are strictly controlled so that they “fire” only once per cell cycle
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Errors of DNA Replication and Disease
The rate of misincorporation of bases by DNA polymerase is extremely low, however repeated sequences can cause problems
In particular, trinucleotide repeats cause difficulties which can lead to expansion of these sequences.
Depending where the repeat is located expansion of the sequence can have severe effects on the expression of a gene or the function of a protein.
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Several inherited diseases are associated with expansion of trinucleotide repeat sequences.
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Have no fear…it’s efficient!! Check out these stats…
Polymerase III
It’s fast: up to 1,000 dNTPs added/sec/enzyme
It’s highly processive: >500,000 dNTPs added before
dissociating
It’s accurate: makes 1 error in 107 dNTPs added, with
proofreading, this gives a final error rate of 1 in 1010 overall.