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BIOLOGY 1A03 Lecture Notes - Central Dogma Of Molecular Biology, Norman Horowitz, Messenger Rna

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Lovaye Kajiura

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Biology Chapter 15: How Genes Work
What Genes Do
George Beadle and Edward Tatum studied how genes work
Beadle said, “one ought to be able to discover what genes do by making them
The idea was to knock out a gene by damaging it and then infer what the gene does by
observing the phenotype of the mutant individual
Today, alleles that do not function at all are called knock-out mutants, null mutants or
loss-of-function mutants
Their experiments on N. crassa inspired their one-gene, one-enzyme hypothesis
They proposed that the mutant N. crassa individual could not make pyridoxine because
it lacked an enzyme required to synthesize the compound and that the lack of enzyme
was due to a genetic defect
Based on analyses of knock-out mutants, the one-gene, one-enzyme hypothesis
claimed that genes contain the information needed to make proteins, many of which
function as enzymes
Later work by Adrian Srb and Norman Horowitz on N. crassa supported the one-gene,
one-enzyme hypothesis
Also showed that genes are responsible for all the different types of proteins produced
by cells, not just enzymes
The Central Dogma of Molecular Biology
The question was, how does a gene specify the production of a protein?
Given DNA’s structure, it appeared extremely unlikely that DNA directly catalyzed the
reactions that produced proteins
Its shape was too regular to suggest that it could bind a wide variety of substrate
molecules and lower the activation energy for chemical reactions
Instead, Crick proposed that the sequence of DNA might act as a code
The idea was that DNA was only an information-storage molecule
The instructions it contained would have to be read and then translated into proteins
Crick’s idea was that different combinations of bases could specify the 20 amino acids
just as different combinations of dots and dashes specify the 26 letters of the alphabet
A particular stretch of DNA could then contain the information needed to specify the
amino acid sequence of a particular enzyme
It soon became apparent, however, that the information encoded in the base sequence
of DNA is not translated into the amino acid sequence of proteins directly
Instead, the link between DNA as information repository and proteins as cellular
machines is indirect
RNA as the Intermediary between Genes and Proteins
o DNA is enclosed within the nucleus
o However, ribosomes, where protein synthesis takes place, are outside the
nucleus, in the cytoplasm
o Francois Jacob and Jacques Monod suggested that RNA molecules act as a link
between genes and the protein-manufacturing centres
o They predicted that short-lived molecules of RNA, called messenger RNA or
mRNA, carry information from DNA to the site of protein synthesis
o Follow-up research confirmed that the mRNA hypothesis is correct
o One particular piece of evidence was the discovery of an enzyme that catalyzes
the synthesis of RNA
o This protein is called RNA polymerase because it polymerizes Ribonucleotides
into strands of RNA
o The key observation was that RNA polymerase synthesizes RNA molecules
according to the information provided by the sequence of bases in a particular
stretch of DNA
o Unlike DNA polymerase, RNA polymerase does not require a primer to begin
adding Ribonucleotides to a growing strand of RNA
The Central Dogma
o The central dogma summarizes the flow of information in cells
o It simply states that DNA codes for RNA, which codes for protein
o DNA RNA proteins
o DNA is the hereditary material
o Genes consist of specific stretches of DNA that code for products used in the cell
o The sequence of bases in DNA specifies the sequences of bases in an RNA
molecule, which specifies the sequence of amino acids in a protein
o In this way, genes ultimately code for proteins
o Biologists used specialized vocabulary to summarize the sequence of events
encapsulated in the central dogma
o For example, biologists say that DNA is transcribed to RNA
o In everyday English, the word transcription simply means making a copy of
o The scientific use of the term is appropriate because DNA acts as a permanent
record, an archive or blueprint containing the information needed to build and
run the cell
o This permanent record is copied, via transcription, to the short-lived form called
o The information is then transferred to a new molecular form, a sequence of
amino acids
o In everyday English, the word translation refers to the transferring of
information from one language to another
o In biology, the synthesis of protein from mRNA is called translation
o Translation is the transferring of information from one type of molecule to
o DNA (information storage) (transcription) mRNA (information carrier)
(translation) Proteins (active cell machinery)
o According to the central dogma, an organism’s genotype is determined by the
sequence of bases in its DNA while its phenotype is a product of the protein it
o Later work revealed that alleles of the same gene differ in their DNA sequence
o As a result, proteins produced by different alleles of the same gene frequently
differ in their amino acid sequence
o If primary structures of proteins vary, their functions are likely to vary as well
The Genetic Code
The genetic code is the rules that specify the relationship between a sequence of
nucleotides in DNA or RNA and the sequence of amino acids in a protein
How long a word is in the genetic code
o Based on some simple logic, George Gamow suggested that each code word
contains three bases
o His reasoning derived from the observation that there are 20 amino acids
commonly used in cells
o Because there are only four bases in Ribonucleotides (A, U, C, G), a three base
code could specify 64 (4 X 4 X 4) different amino acids
o As a result, a three-base code would provide more than enough messages to
code for all 20 amino acids
o This three-base code is known as the triplet code
o Gamow’s hypothesis predicted that the genetic code is redundant
o That is, more than one triplet of bases might specify the same amino acid
o A group of three bases that specifies a particular amino acid is called a codon
o Work by Francis Crick and Sydney Brenner confirmed that codons are three
bases long
o Their experiments used chemicals that caused an occasional addition or
deletion of a base in DNA
o As predicted for a triplet code, a one-base addition or deletion in the base
sequence led to a loss of function in the gene being studied
o This is because a single addition or deletion mutation throws the reading frame
out of register
o Crick and Brenner used chemicals to remove one, two or three bases from the
parent sequence
o A one or two base deletion resulted in a non functional protein being produced
o When three bases were deleted, a slightly altered, but functional protein was
How researchers cracked the code
o Marshall Nirenberg and Heinrich Matthaei created a method for synthesizing
RNAs of known sequence
o Their method was based on an enzyme called polynucleotide phosphorylase,
which catalyses the formation of phosphodiester bonds between any
ribonucleotides available, in random order
o By providing ribonucleotides whose only base was Uracil to a reaction mix
containing this enzyme, they were able to create a long polymer of Uracil-
containing ribonucleotides
o The researchers analyzed the resulting amino acid sequence and determined
that it was polyphenylalanine, a polymer consisting of amino acid phenylalanine
o Thus, UUU codes for phenylalanine
o By complementary base pairing, it was clear that the corresponding DNA
sequence would be AAA, which produced polypeptides consisting of lysine
o Poly-C RNA’s produced polypeptides composed entirely of proline
o They also later devised a system for synthesizing specific codons