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CHAPTER 5 DNA REPLICATION, REPAIR AND RECOMBINATION. THE MAINTENANCE OF DNA SEQUENCES DNA REPLICATION MECHANISMS THE INITIATION AND COMPLETION OF DNA REPLICATION IN CHROMOSOMES DNA REPAIR GENERAL RECOMBINATION SITE-SPECIFIC RECOMBINATION. THE MAINTENANCE OF DNA SEQUENCES.

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Chapter 5 dna replication repair and recombination l.jpg
CHAPTER 5 DNA REPLICATION, REPAIR AND RECOMBINATION

  • THE MAINTENANCE OF DNA SEQUENCES

  • DNA REPLICATION MECHANISMS

  • THE INITIATION AND COMPLETION OF DNA REPLICATION IN CHROMOSOMES

  • DNA REPAIR

  • GENERAL RECOMBINATION

  • SITE-SPECIFIC RECOMBINATION


The maintenance of dna sequences l.jpg
THE MAINTENANCE OF DNA SEQUENCES

  • Mutation Rates Are ~1/109 bp

  • Inherent fidelity of DNA polymerase is ~ 1/106 bp

  • Other mechanisms, proofreading and repair are necessary

  • Low Mutation Rates Are Necessary for Life as We Know It


Mutation rates are relatively constant but proteins evolve at different rates l.jpg
Mutation rates are relatively constant but proteins evolve at different rates

  • Proteins evolve different at different rates depending on structural and functional constrains

  • In some proteins most changes interfere with function

  • In others many sequence changes are tolerated


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DNA REPLICATION MECHANISMS at different rates

  • Base-pairing Underlies DNA Replication and DNA Repair

  • DNA Replication is always in the 5’-to-3’ Direction

  • The DNA Replication Fork Is Asymmetrical

  • Fidelity of DNA Replication Requires Several Proofreading Mechanisms






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The DNA Replication Fork Is Asymmetrical at different rates

  • Leading and lagging strands have different requirements


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Accesssory proteins at different rates

  • DNA Primase Synthesizes Short RNA Primer Molecules on the Lagging Strand

  • Helicases - Open Up the DNA Double Helix in Front of the Replication Fork

  • Single strand binding proteins keep ssDNA out of trouble

  • Clamp subunits tether A Moving DNA Polymerase to the DNA

  • The Proteins at a Replication Fork Cooperate to Form a Replication Machine










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Other factors operate away from the replication fork specialization

  • A Strand-directed Mismatch Repair System Removes Replication Errors That Escape from the Replication Machine

  • DNA Topoisomerases Prevent DNA Tangling During Replication

    • All topoisomerases form transient covalent phospho-tyrosine bonds to DNA backbone

    • Type 1 topoisomerase nicks only one strand - unwinds only

    • Type 2 topoisomerase nicks both strands - unwinds and untangles - Makes DNA “ethereal”


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A Strand-directed Mismatch Repair System Removes Replication Errors That Escape from the Replication Fork


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DNA Topoisomerase Prevents DNA Tangling During Replication Errors That Escape from the Replication Fork


Type 1 topoisomerase nicks only one strand unwinds only l.jpg
Type 1 topoisomerase nicks only one strand - unwinds only Errors That Escape from the Replication Fork


Type 2 topoisomerase nicks both strands unwinds and untangles makes dna ethereal l.jpg
Type 2 topoisomerase nicks both strands - Errors That Escape from the Replication Fork Unwinds and Untangles - Makes DNA “ethereal”


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THE INITIATION OF DNA REPLICATION Errors That Escape from the Replication Fork

  • DNA Synthesis Begins at Replication Origins

    • BacteriaHave a Single Origin

    • Eucaryotic Chromosomes Contain Multiple Origins

  • In Eucaryotes DNA Replication Takes Place During Only One Part of the Cell Cycle

  • Different Regions on the Same Chromosome Replicate at Distinct Times in S Phase

  • Highly Condensed Chromatin Replicates Late,While Genes in Less Condensed Chromatin Tend to Replicate Early


Dna synthesis begins at replication origins l.jpg
DNA Synthesis Begins at Replication Origins Errors That Escape from the Replication Fork


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BacteriaHave a Single Origin Errors That Escape from the Replication Fork



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Origins can be mapped by pulse labeling controlled by methylation


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Different DNA regions have distinct timings of replication during the S phase of the eukaryotic cell cycle


Well defined dna sequences serve as replication origins in a simple eucaryote the budding yeast l.jpg
Well-defined DNA Sequences Serve as Replication Origins in a Simple Eucaryote, the Budding Yeast

  • A Large Multisubunit Complex Binds to Eucaryotic Origins of Replication

  • The Mammalian DNA Sequences That Specify the Initiation of Replication Have Been Difficult to Identify

  • New Nucleosomes Are Assembled Behind the Replication Fork


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Yeast Origins have been identified by genetic means Simple Eucaryote, the Budding Yeast




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COMPLETION OF DNA REPLICATION IN CHROMOSOMES Replication

  • Telomerase Replicates the Ends of Chromosomes

  • Telomere Length Is Regulated by Cells and Organisms





Many somatic cells have low telomerase atctivity some cancer cells have enhanced acivity l.jpg
Many Somatic Cells have low telomerase atctivity, Some cancer cells have enhanced acivity


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DNA REPAIR cancer cells have enhanced acivity

  • Without DNA Repair, Spontaneous DNA Damage Would Rapidly Change DNA Sequences

  • The DNA Double Helix Is Readily Repaired

  • DNA Damage Can Be Removed by More Than One Pathway

  • The Chemistry of the DNA Bases Facilitates Damage Detection

  • Double-Strand Breaks are Efficiently Repaired

  • Cells Can Produce DNA Repair Enzymes in Response to DNA Damage

  • DNA Damage Delays Progression of the Cell Cycle



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Depurination and Cytosine Deamination cancer cells have enhanced acivity


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Replication “fixes” mutations on one strand cancer cells have enhanced acivity


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Thymine dimers can be formed after UV irradiation cancer cells have enhanced acivity


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Excision repair cancer cells have enhanced acivity


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Double-strand breaks are the most serious lesions cancer cells have enhanced acivity


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GENERAL RECOMBINATION cancer cells have enhanced acivity

  • General Recombination Is Guided by Base-pairing Interactions Between Two Homologous DNA Molecules

  • Meiotic Recombination Is Initiated by Double-strand DNA Breaks

  • DNA Hybridization Reactions Provide a Simple Model for the Basepairing Step in General Recombination

  • The RecA Protein and its Homologs Enable a DNA Single Strand to Pair with a Homologous Region of DNA Double Helix

  • There Are Multiple Homologs of the RecA Protein in Eucaryotes, Each Specialized for a Specific Function

  • General Recombination Often Involves a Holliday Junction

  • General Recombination Can Cause Gene Conversion

  • General Recombination Events Have Different Preferred Outcomes in Mitotic and Meiotic Cells

  • Mismatch Proofreading Prevents Promiscuous Recombination Between Two Poorly Matched DNA Sequences


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Homologous recombination repairs spontaneous breaks in DNA and those induced in Meiotic crossing-over


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Synapsis: and those induced in Meiotic crossing-overAlignment of complementary DNA strands by base pairing


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Structure and Mechanism of the RecA protein from E. coli and those induced in Meiotic crossing-over


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Robin and those induced in Meiotic crossing-overHolliday’s Model for a double strand crossover junction




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Recombination between repeated sequences can lead to deletions and inversions: Mismatch detection minimizes aberrant recombination


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SITE-SPECIFIC RECOMBINATION deletions and inversions: Mismatch detection minimizes aberrant recombination

  • Mobile Genetic Elements Can Move by Either Transpositional or Conservative Mechanisms

  • Transpositional Site-specific Recombination Can Insert a DNA Element into Any DNA Sequence

  • DNA-only Transposons Move By DNA Breakage and Joining Reactions

  • Some Viruses Use Transpositional Site-specific Recombination to Move Themselves into Host Cell Chromosomes

  • Retroviral-like Retrotransposons Resemble Retroviruses, but Lack a Protein Coat

  • A Large Fraction of the Human Genome Is Composed of Nonretroviral Retrotransposons

  • Different Transposable Elements Predominate in Different Organisms

  • Genome Sequences Reveal the Approximate Times when Transposable Elements Have Moved

  • Conservative Site-specific Recombination Can Reversibly Rearrange DNA

  • Conservative Site-Specific Recombination Can be Used to Turn Genes On or Off


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Mobile DNA elements in bacteria deletions and inversions: Mismatch detection minimizes aberrant recombination

Insertion sequences

Cis acting DNA sites - end sequences (red)

Trans-acting Protein factors - transposase (blue)

Transposons are compound elements


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Transposition Mechanisms: deletions and inversions: Mismatch detection minimizes aberrant recombinationReplicative and non replicative


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RNA elements : retroviruses and retrotransposons deletions and inversions: Mismatch detection minimizes aberrant recombination


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Repeat orientation determines recombination outcome deletions and inversions: Mismatch detection minimizes aberrant recombination


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Lambda Life Cycle deletions and inversions: Mismatch detection minimizes aberrant recombination

coordinated transcription and site specific recombination


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Site-specific recombination by deletions and inversions: Mismatch detection minimizes aberrant recombination l integrase


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Bacteriophage Mu deletions and inversions: Mismatch detection minimizes aberrant recombination

Transposase is encoded by A and B genes

C represses expression of (almost) all other genes

Gin is a site specific recombinase


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Mu replicates by transposition deletions and inversions: Mismatch detection minimizes aberrant recombination

The Mu C protein (AKA Repressor, Rep) is analogous to the lambda repressor

TS mutants repress at the permissive temperature but fail to function at higher temperatures.


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