Genetic Regulation

DNA: Desoxirribonucleic Acid
1. Polymere of Nucleotides
2. Watson & Crick's Model
  1. Double Helix Structure
    1. Back Bone (outside): Sugar + Phosphate
    2. (inside) Paired Bases
      1. Double Ring: Purine Bases
        Adenine (A)
        Guanine (G)
      2. Single Ring: Pyrimidine Bases
        Thymine (T)
        Cytosine (C)
        Chargaff's Rules
        1. the amount of A, T, G, C in DNA varies from specie to specie
        2. in each species the amount of A=T and the amount of G=C
        Structure
        COMPLEMENTARY PAIRING: A is always bonded to T & G is always bonded to C by a hydrogen bond
        A purine (wide) is always paired to a pyrimidine (narrow) to complement sizes
        Strands with ANTI PARALLEL ARRANGEMENT
        Every nucleotide has a phosphate group at the 5' position of the sugar & they bind together by linking this 5' phosphate to the free hydroxyl (--OH) at the 3' position of the other nucleotide's sugar (giving it it's direction)
        DOGMA OF MOLECULAR BIOLOGY
        Replication: Copying a DNA molecule
        DNA replication is termed semi-conservative replication because each daughter DNA double helix contains an old strand from the parental DNA double helix and a new strand
        STEPS:
        1. Unwinding: an enzyme called helicase breaks the hydrogen bond between the paired bases (creating a replication fork)
        2. Complementary Base Pairing: New complementary nucleotides, always present in the nucleus, are positioned in place (by an enzyme complex called DNA polymerase)
        3. Joining: new strands are crated so each daughter DNA molecule contains an old and a new strand (by an enzyme complex called DNA polymerase)
        DNA ligase, joins the fragments, but there is no way for DNA polymerase to replicate the 5' ends of both new strands after RNA primers are removed. So DNA molecules get shorter as one replication follows another.
        the leading new strand continues it's normal process, the lagging strand is discontinuous, the segments are known as Okazaki Fragments. as the RNA primers are replaced by the nucleotides.
        A DNA polymerase is very accurate and makes a mistake approximately once per 100,000 base pairs at most.
        Differences between...
        Eukaryotes
        Telomeres (special nucleotide sequence at the end of the DNA) do not code for proteins, instead creates repeats of a short nucleotide sequence, such as TTAGGG.
        replication may begin at numerous origins
        the process can take hours because of the amount of info replicated
        Prokaryotes
        Bacteria have a single circular loop of DNA, replication moves around the DNA molecule in one direction only.
        it requires 40 min. to replicate & can do so every 20 min.
        it is possible for a new round of DNA replication to begin even before the previous round is complete.
        Transcription
        1st step in syntetization of a protein: DNA serves as a template for RNA formation.
        pre-mRNA if formed (by RNA Polymerase when it ataches to a DNA promoter)
        RNA (Ribonucleic Acid) carries the information
        Polymere composed of nucleotides: sugar ribose & bases.
        Structure: single stranded, NO double helix
        typically has a poly a tail (has many adenine nucleotides at one end & a cap at the other end)
        Adenine (A), Guanine (G), Uracil (U), Cytosine (C)
        Types of RNA
        Messenger RNA (mRNA) takes a message from DNA in the nucleus to the ribosomes in the cytoplasm.
        Transfer RNA (tRNA) transfers amino acids to the ribosomes
        Ribosomal RNA (rRNA), along with ribosomal proteins, makes up the ribosomes, where polypeptides are synthesized.
        Codon (triplet code): 3 nucleotide bases
        properties
        1. The genetic code is degenerate. most amino acids have more than one codon; (leucine, serine, and arginine have six different codons)
        The degeneracy of the code protects against potentially harmful effects of mutations.
        2. The genetic code is unambiguous. Each triplet codon has only one meaning.
        3. The code has 1 start and 3 stop signals.
        elongation of the mRNA continues until DNA reaches a stop point & the mRNA is liberated = mRNA Transcript
        made up of nucleotides & regions called: exons and introns
        splicing: introns are removed (forming an mRNA: template to form proteins)
        m RNA will leave the nucleus through the nuclear pore into the cell's cytoplasm
        Prokatyotes have self-spllicing: the intron itself has the capability of enzymatically splicing itself out of a premRNA.
        Another type of RNA called small nucleolar RNA (snoRNA) is present in the nucleolus, where it helps process rRNA and tRNA molecules.
        Eukaryotes: splicing is done by spliceosomes, which contain small nuclear RNAs (snRNAs: are capable of identifying the introns to be removed) A spliceosome utilizes a ribozyme when it removes the introns.
        REGULATION OF GENE ACTIVITY
        Prokaryote Regulation
        Operon Model
        Promoter: signals where transcription is to begin.
        Operator: controls transcription of structural genes.
        active repressor binds to the operator, RNA polymerase cannot attach to the promoter, and transcription cannot occur
        Structural Genes: instructions to primary structure of enzymes in a metabolic pathway
        Regulator Gene: codes for a repressor that controls whether the operon is active or not.
        Trp Operon (repressible system)
        when the active repressor binds to the operator transcription is prevented because RNA polymerase can't bind to the promoter
        gene expression "on" by default the corepressor can bind to the repressor activating it causing expresion to go off
        only on/off (negative gene regulation)
        Lac Operon (inducible systems)
        on/ off (negative gene regulation)
        gene expression "off" by default corepressor binds to repressor deactivating it and turnig expresion "on" by unbinding it form the operator
        by unbinding the repressor from the promoter expression is allowed
        up/ down (positive gene regulation)
        there are no repressors, just activators
        there's some level of transcription but we need more
        cyclic amp activates the activator by binding to it and changing it's form so it can bind with the promoter and increase transctription
        Eukaryote Regulation
        1. Chromatin Structure
        core of 8 histone proteins wraped around by DNA
        the DNA packed around the histone can't be transcribed
        chromatin remodeling complex can liberate the DNA making it transcribable
        Heterochromatin: strongly packed histones
        Euchromatin: loosely packed histones
        Epigenetic inheritance: When histones are methylated, sometimes the DNA itself becomes methylated as well = genetic imprinting, expression depends if the gene is inherited from the mother or father, not the gene it self
        2. Transcriptional Control
        transcription factors: proteins that help regulate transcription
        transcription activators are DNA binding proteins that speed transcription dramatically.
        transcription factors bind to the promoter and transcription activators bind to an enhancer when the loop is formed to allow transcription to begin
        3. Posttranscriptional Control
        occurs in the nucleus and includes alternative mRNA splicing and controlling the speed with which mRNA leaves the nucleus.
        pre-mRNA has introns and exons, introns stay in the nucleus as exons exit the nucleous = mRNA
        4. Translational Control
        mRNA strands after splicing are too short so they become...
        micro RNA's, they are double stranded and where turned off, micro RNA can lower the expression of genes
        5. Posttranslational Control
        the last chance a cell has for influencing gene expression
        Some proteins are not immediately active after synthesis.
        some proteins only become active when it is appropriate for them to do so.
        Gene Mutations
        permanent change in the sequence of bases in DNA
        Causes
        Spontaneous mutations
        the movement of transposons from one chromosomal location to another can disrupt a gene and lead to an abnormal product.
        a base in DNA can undergo a chemical change that leads to a miss pairing during replication and may be carried in future generations.
        they are extremely rare, 1 billion nucleotide pairs replicated.
        Induced Mutations
        caused by mutagens, environmental factors that can alter the base composition of DNA
        Many mutagens are also carcinogens (cancer-causing)
        industrial chemicals, foods, tabacco, radiation
        Effects
        on Protein Activity
        point mutation: e a change in a single DNA nucleo - tide and, therefore, a possible change in a specific amino acid.
        can range in effect, depending on the particular codon change
        Frameshift mutation: one or more nucleotides are either inserted or deleted from DNA.
        The result can be a completely new sequence of codons and nonfunctional protein
        Non-Functional Proteins
        dramatic effect on the phenotype, because enzymes are often a part of metabolic pathways.
        Mental retardation, albinism, PKU, etc.
        Cancer
        The development of cancer involves a series of accumulating mutations that can be different for each type of cancer
        tumor suppressor genes are inactive and oncogenes are active
        cell division occurs uncontrollably because a cell signaling pathway that reaches from the plasma membrane to the nucleus no longer functions as it should
        Translation
        2nd step in syntetization of a protein: the mRNA transcript directs the sequence of amino acids in a polypeptide.
        cell changes a nucleotide sequence into an amino acid sequence. With the help of the three types of RNA, a gene (a segment of DNA) specifies the sequence of amino acids in a polypeptide
        A tRNA molecule is a single-stranded nucleic acid that doubles back on itself to create regions where complementary bases are hydrogen-bonded to one another
        there's at least 1 for every amino acid in the protein, it binds to the 3' end.
        on the 5' end, an anti codon (group of three bases complementary to a specific mRNA codon so that they pair in an antiparallel fashion)
        fewer tRNAs that codos because of the wobble hypothesis.
        the first two positions in a tRNA anticodon pair obey the A–U/G–C configuration, but the third position can be variable. This helps ensure that despite changes in DNA base sequences, the correct sequence of amino acids will result in a protein
        aminoacyl-tRNA synthetase (enzyme found in the cytoplasm) attaches a different type of aminoacid to the specific tRNA
        this process uses ATP
        amino acid–tRNA complex is formed
        travels to a ribosome
        formation in eukaryotes: rRNA spliced to form 2 rRNA strtands, 1 small & 1 big
        produced from a DNA template in the nucleolus of a nucleus, synthetised by RNA polymerase I
        they leave the nucleolus & fold to form a small and large sub unit of the ribosome = pre-ribosome (still inside the nucleus)
        they leave the nucleous and the ribosome can either stay un the cytoplasm or get attatchd to the ER
        the small and large sub units of the ribosome attach to the cap of the mRNA
        Translation begins
        STAGE 1 Initiation: Proteins (initiation factors) assemble the small ribosomal subunit and the large ribosomal subunit through the P site of the ribosome, now occupied by the initiator tRNA (with an attached peptide), to the cap of the mRNA
        In prokaryotes, a small ribosomal subunit attaches to the mRNA in the vicinity of the start codon (AUG).The first or initiator tRNA pairs with this codon. Then, a large ribosomal subunit joins to the small subunit
        STAGE 2 Elongation:
        1 tRNA + amino acid arrives at the A site.
        2 ribosome verifies that new tRNA matches the codon and firmly places it at the A site, peptide will transfer to the new tRNA.
        3 the peptide bond formation is one amino acid longer than it was before. creating a protein. (now attached to the new tRNA at A site)
        4 translocation occurs: The ribosome moves forward, and the peptide-bearing tRNA is now at the P site of the ribosome. The spent tRNA is now at the E site, and it exits. :A new codon is at the A site and is ready to receive another tRNA. (this process repeats until the end of mRNA strand)
        STAGE 3 Termination: it occurs at a stop codon (codon that don't code for an amino acid), a protein called a release factor, binded to a stop codon, releases the tRNA at P site and the polypeptide chain. the ribosome separates into 2,
        structure: ribosome has three binding sites for tRNAs.
        E (exit) site
        P (peptide) site
        A (amino acid) site
        DNA synthesised by RNA polymerase III creates the tRNA
        The universal nature of the genetic code provides strong evidence that all living things share a common evolutionary heritage
        . Since the same genetic code is used by all living things, it is possible to transfer genes from one organism to another.

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