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DNA (Ch. 16) (DNA Replication (DNA Replication Process (The DNA…

- - - - In DNA replication, the parent molecule unwinds, and two new daughter strands are built based on base-pairing rules
      - If you cover one of the two DNA strands, you can still determine its linear sequence of nucleotides by referring to the uncovered strand and applying the base-pairing rules (A=T and G=C)
    - - The semiconservative model predicts that when a double helix replicates, each daughter molecule will have one old strand (derived or “conserved” from the parent molecule) and one newly made strand
      - Competing models were the conservative model (the two parent strands rejoin) and the dispersive model (each strand is a mix of old and new)
      - In a third model, called the dispersive model, all four strands of DNA following replication have a mixture of old and new DNA
  - - - Replication begins at particular sites called origins of replication, short stretches of DNA that have specific sequence of nucleotides
      - Proteins that initiate DNA replication recognize this sequence and attach to the DNA, separating the 2 strands and opening up a replication "bubble"
        
        Replication of DNA then proceeds in both directions until the entire molecule is copied
        
        At the end of At the end of each replication bubble is a replication fork, a Y-shaped region where the parental strands of DNA are being unwound
        
        Helicases are enzymes that untwist the double helix at the replication forks
        
        After the parental strands separate, single-strand binding proteins bind to the unpaired DNA strands keeping them from re-pairing.
        
        The untwisting of the double helix causes tighter twisting and strain ahead of the replication fork
        
        Topoisomerase relieves the strain of twisting of the double helix by breaking, swiveling, and rejoining DNA strands
    - - The unwound sections of parental DNA strands are now available to serve as templates for the synthesis of new complementary DNA strands
      - Enzymes that synthesize DNA cannot initiate the synthesis of polynucleotide; they can only add DNA nucleotides to the end of an already existing chain that is base-paired with the template strand
      - DNA polymerases require a primer to which they can add nucleotides
        
        The initial nucleotide strand is a short RNA primer
        
        This is synthesized by the enzyme primase
        
        Primase can start an RNA chain from scratch and adds RNA nucleotides one at a time using the parental DNA as a template
        
        The primer is short (5–10 nucleotides long), and the 3′ end serves as the starting point for the new DNA strand
        
        Enzymes called DNA polymerases catalyze the synthesis of new DNA at a replication fork
        
        Most DNA polymerases require a primer and a DNA template strand, along which complementary DNA nucleotides are lined up
        
        Each nucleotide that is added to a growing DNA strand is a nucleoside triphosphate
        
        dATP supplies adenine to DNA and is similar to the ATP of energy metabolism
        
        The difference is in their sugars: dATP has deoxyribose while ATP has ribose
        
        As each monomer joins the DNA strand, via a dehydration reaction, it loses two phosphate groups as a molecule of pyrophosphate
    - - The 2 ends of a DNA strand are different, giving each strand directionality, like a one-way street
      - 2 new strands formed during the DNA replication must also be antiparallel to their template strands
        
        The antiparallel structure of the double helix affects replication
        
        DNA polymerases add nucleotides only to the free 3′ end of a growing strand; therefore, a new DNA strand can elongate only in the 5′ to 3′ direction
        
        Along one template strand of DNA, the DNA polymerase synthesizes a leading strand continuously, moving toward the replication fork
        
        To elongate the other new strand, called the lagging strand, DNA polymerase must work in the direction away from the replication fork
        
        The lagging strand is synthesized discontinuously, as a series of segments
        
        The segments of the lagging strand are called the Okazaki fragments which are joined together by DNA ligase
    - - The proteins that participate in DNA replication form a large complex, a “DNA replication machine”
      - The DNA replication machine may be stationary during the replication process
      - Recent studies support a model in which DNA polymerase molecules “reel in” parental DNA and extrude newly made daughter DNA molecules
      - The exact mechanism is not yet resolved
  - - - In mismatch repair of DNA, repair enzymes correct errors in base pairing
      - DNA can be damaged by exposure to harmful chemical or physical agents such as cigarette smoke and X-rays; it can also undergo spontaneous changes
    - - The error rate after proofreading and repair is low but not zero
      - Sequence changes may become permanent and can be passed on to the next generation
      - These changes (mutations) are the source of the genetic variation upon which natural selection operates and are ultimately responsible for the appearance of new species
  - - - It has been proposed that the shortening of telomeres is connected to aging
      - If chromosomes of germ cells became shorter in every cell cycle, essential genes would eventually be missing from the gametes they produce
      - An enzyme called telomerase catalyzes the lengthening of telomeres in germ cells
      - The shortening of telomeres might protect cells from cancerous growth by limiting the number of cell divisions
- - - - Eukaryote:
        
        Chromosomes may have hundreds or even a few thousand replication origins (multiple)
      - Prokaryote:
        
        Chromosomes are circular and has a single origin
  - - - Include point mutations, changes in a single nucleotide gene
      - Small scale mutations within a protein-coding genes
        
        Single nucleotide-pair substitution
        
        A change in a nucleotide pair may transform one codon into another that is translated into the same amino acid
        
        A nucleotide-pair substitution is the replacement of one nucleotide and its partner with another pair of nucleotides
        
        The nucleotide-pair substitutions greatest interest are those that cause a major in a protein
        
        Nucleotide-pair insertions or deletions
        
        Insertions and deletions are additional losses of nucleotide pairs in a gene
        
        These mutations have a disastrous effect on the resulting protein more often than substitutions do
        
        Insertion or deletion of nucleotide may alter the reading frame of the genetic message, the triplet grouping of nucleotides on the mRNA that is read translation
        
        Such a mutation, called a frameshift mutations occurs whenever the number of nucleotides inserted or deleted is not a multiple of three
    - - There is some evidence that some silent mutations may indirectly affect where or what level the gene gets
      - Expressed, even though the actual protein is the same
    - - Such a mutation has little effect on the protein
      - The new amino acid may have properties similar to those of the amino acid it replaces, or it may be in a region of the protein where the exact sequence of amino acids is not essential to proteins function
    - - A nonsense mutation causes translation to be terminated prematurely; the resulting polypeptide will be shorter than the polypeptide encoded by the normal gene
      - Most nonsense mutations lead to a nonfunctional proteins
- - - - When he mixed heat-killed remains of the pathogenic strain with living cells of the harmless strain, some living cells became pathogenic
      - He called this phenomenon transformation, now defined as a change in genotype and phenotype due to assimilation of foreign DNA
      - Later work by Oswald Avery, Maclyn McCarty, and Colin MacLeod identified the transforming substance as DNA
    - - More evidence for DNA as the genetic material came from studies of viruses that infect bacteria
        
        Such viruses, called bacteriophages (or phages), are widely used in molecular genetics research
        
        A virus is DNA (sometimes RNA) enclosed by a protective coat, often simply protein
      - In 1952, Alfred Hershey and Martha Chase showed that DNA is the genetic material of a phage known as T2 (a type of phage that infects E.coli)
        
        They designed an experiment showing that only one of the two components of T2 (DNA or protein) enters an E. coli cell during infection
        
        They concluded that the injected DNA of the phage provides the genetic information
      - Additional Evidence That DNA is the Genetic Material
        
        It was known that DNA is a polymer of nucleotides
        
        The nitrogenous bases can be adenine (A), thymine (T), guanine (G), or cytosine (C)
        
        Each consisting of a nitrogenous base, a sugar, and a phosphate group
        
        In 1950, Erwin Chargaff reported that DNA composition varies from one species to the next
        
        This evidence of diversity made DNA a more credible candidate for the genetic material
        
        Chargaff also noticed a pattern in the ratios of nucleotide bases
        
        In the DNA of each species he studied, the # of adenine approximately equaled the # of thymines, & the # of guanines approximately equaled the # of cytosines
        
        These 2 findings became known as Chargaff's rules:
        
        DNA base composition varies between species, and
        
        for each species, the percentage of A and T bases are roughly equal, as are those of G and C bases
        
        The basis for these rules was not understood until the discovery of the double helix
        
        Structure of DNA
        
        After DNA was accepted as the genetic material, the challenge was to determine how its structure accounts for its role in heredity
        
        Maurice Wilkins and Rosalind Franklin were using a technique called X-ray crystallography to study molecular structure
        
        Franklin produced a picture of the DNA molecule using this technique
        
        Franklin’s X-ray crystallographic images of DNA enabled Watson to deduce that DNA was helical
        
        The X-ray images also enabled Watson to deduce the width of the helix and the spacing of the nitrogenous bases
        
        The pattern in the photo suggested that the DNA molecule was made up of two strands, forming a double helix
        
        Watson and Crick built models of a double helix to conform to the X-rays and chemistry of DNA
        
        Franklin had concluded that there were two outer sugar-phosphate backbones, with the nitrogenous bases paired in the molecule’s interior
        
        Watson built a model in which the backbones were antiparallel (their subunits run in opposite directions)
        
        At first, Watson and Crick thought the bases paired like with like (A with A, and so on), but such pairings did not result in a uniform width
        
        Instead, pairing a purine (A or G) with a pyrimidine (C or T) resulted in a uniform width consistent with the X-ray data
        
        Watson and Crick reasoned that the pairing was more specific, dictated by the base structures
        
        They determined that adenine (A) paired only with thymine (T), and guanine (G) paired only with cytosine (C)
        
        The Watson-Crick model explains Chargaff’s rules: in any organism the amount of A = T, and the amount of G = C
- - - - Histones can undergo chemical modifications that result in changes in chromatin condensation
      - These changes can also have multiple effects on gene expression
    - - They are composed of two each of the four basic histone types, with DNA wrapped twice around the core of the eight histones
      - The N-termini (“tails”) of the histones protrude from the nucleosome
      - Nucleosomes, and especially their histone tails, are involved in the regulation of gene expression
      - Most chromatin is loosely packed in the nucleus during interphase and condenses prior to mitosis
        
        Loosely packed chromatin is called euchromatin
        
        During interphase a few regions of chromatin (centromeres and telomeres) are highly condensed into heterochromatin
        
        Dense packing of the heterochromatin makes it difficult for the cell to express genetic information coded in these regions