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THE MOLECULAR BASIS OF INHERITANCE (Many proteins work together in DNA…
THE MOLECULAR BASIS OF INHERITANCE
DNA IS THE GENETIC MATERIAL
Griffith: studied two bacterial strains, one pathogenic and one non-pathogenic
He found that when he heat-killed some of the pathogenic bacteria, then mixed the dead cells with the living non-pathogenic bacteria, and some of the living cells became pathogenic
These newly pathogenic cells gave rise to offspring that were also pathogenic
He concluded that some chemical component of the dead pathogenic bacteria must’ve caused this trait
This phenomenon was called
transformation
, which is now defined as a change in genotype and phenotype due to the assimilation of external DNA by a cell
Despite Griffith’s experiment, scientists still thought proteins were the genetic material
Another study into
bacteriophages
(bacteria-infecting viruses) by Hershey and Chase used radioactivate phosphorus found only in DNA and radioactive sulphur found only in proteins, and determined DNA to be the genetic material
Concluded that phages must have injected the genetic molecule DNA into the new cells to produce more viral DNA and proteins
Chargaff observed that the base composition of DNA varies from one species to another, and that there was a ratio of the number of bases; that is, the number of A=T and G=C (approximately at least)
Chargaff’s rules:
the base composition of DNA varies between species
For each species, the percentage of A and T bases are roughly equal and the percentages of G and C bases are roughly equal
Building a structural model of DNA: scientific Inquiry
Franklin contributed to the double helix model
Her model put the relatively hydrophobic nitrogenous bases in the molecule’s interior, away from the surrounding aqueous solution, and the negatively charged phosphate groups wouldn’t be forced together in the interior
The two sugar-phosphate backbones are
antiparallel:
their subunits run in opposite directions
Adenine (A) pairs with thymine (T) and guanine (G) pairs with cytosine (C)
Adenine and guanine are
purines
, nitrogenous bases with two organic rings
while cytosine and thymine are nitrogenous bases called pyrimidines, which have just one single ring
Therefore, purine pairs with pyrimidine
A-T bond has two hydrogen bonds, G-C bond has three hydrogen bonds
Many proteins work together in DNA replication and repair -
The basic principle: base pairing produces a template strand
Semiconservative model
: Type of DNA replication in which the replicated double helix consists of one old strand, derived from the parental molecule, and one newly formed strand
This model differs from the conservative model in which the two parental strands reassociate after acting as templates for new strands, restoring the parental double helix, and also the dispersive model in which each strand of both daughter molecules contains a mixture of old and newly synthesised DNA
DNA Replication: a closer look
The copying of DNA is remarkably accurate and fast
Many enzymes and proteins participate in DNA replication
Replication models are based off E. coli but can be extended to other prokaryotes and even eukaryote
prokaryotic DNA replication
Helicase separates the DNA to form a replication fork at the origin of replication where DNA replication begins.
Replication forks extend bi-directionally as replication continues
Okazaki fragments are formed on the lagging strand, while the leading strand is replicated continuously.
DNA ligase seals the gaps between the Okazaki fragments.
Primase synthesizes an RNA primer with a free 3′-OH, which DNA polymerase III uses to synthesize the daughter strands.
DNA replication in Eukaryotes
During initiation, proteins bind to the origin of replication while helicase unwinds the DNA helix and two replication forks are formed at the origin of replication.
During elongation, a primer sequence is added with complementary RNA nucleotides, which are then replaced by DNA nucleotides.
During elongation the leading strand is made continuously, while the lagging strand is made in pieces called Okazaki fragments.
During termination, primers are removed and replaced with new DNA nucleotides and the backbone is sealed by DNA ligase.
Getting Started
The replication of a chromosome begins at particular sites called
origins of replication
, short stretches of DNA having a specific sequence of nucleotides
At each end of replication bubble is a
replication fork
, a Y-shaped region where the parental strands of DNA are being unwound.
several kinda of proteins participate in the unwinding
Helicases:
are enzymes that untwist the double helix at the relication forks, separating two parental strands and making them available as template strands.
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 relication fork
Topoisomerase
is an enzyme that helps relieve this strain by breaking, swiveling and rejoining DNA strands.
Synthesizing a new DNA strand
DNA polymeras
e. DNA polymerases are responsible for synthesizing DNA: they add nucleotides one by one to the growing DNA chain, incorporating only those that are complementary to the template.
key features of DNA polymerases:
They always need a template
They can only add nucleotides to the 3' end of a DNA strand
They can't start making a DNA chain from scratch, but require a pre-existing chain or short stretch of nucleotides called a
primer
They proofread, or check their work, removing the vast majority of "wrong" nucleotides that are accidentally added to the chain
Primase
makes an RNA primer, or short stretch of nucleic acid complementary to the template, that provides a 3' end for DNA polymerase to work on
DNA pol III : Using parental DNA as a template, synthesises new DNA strand by adding nucleotides to an RNA primer or a pre-existing DNA stran
DNA pol I : removes RNA nucleotides of primer from 5’ end and replaces them with DNA nucleotide
Antiparallel Elongation
The two strands of DNA in a double helix are antiparallel, meaning that they are orientated in opposite directions to each other, like the lanes of a divided highway
DNA polymerases can only add nucleotides to the free 3’ end of a primer or growing DNA strand, never to the 5’ end -
Therefore, a new DNA strand can only elongate in the 5’ 3’ direction
Along one template strand, DNA pol III can synthesis a complementary strand continuously by elongating the new DNA in the mandatory 5’ 3’ direction
DNA pol III remains in the replication fork on that template strand and continuously adds nucleotides to the new complementary strand as the fork progresses
The DNA strand made by this mechanism is called the
leading strand.
Only one primer is required to synthesis the entire leading strand
To elongate the other new strand of DNA in the mandatory 5’3’ direction, DNA pol III must work away from the other temperate strand in the direction away from the replication fork
The DNA strand elongated in this direction is called the
lagging strand
The leading strand elongates continuously, while the lagging strand is synthesised discontinuously, as a series of segments
these segments of the lagging strand are called
Okazaki fragments
Whereas only one primer is required for the leading strand, each Okazaki fragment on the lagged strand must be primed separately
After DNA pol III forms an Okazaki fragment, another DNA polymerase, DNA pol I, replaces the RNA nucleotides of the adjacent primer with DNA nucleotides
But DNA pol I cannot join the final nucleotide of this replacement DNA segment to the first DNA nucleotide of the adjacent Okazaki fragment
Another enzyme,
DNA ligase
, accomplishes this task, joining the sugar-phosphate backbones of all the Okazaki fragments into a continuous DNA strand
Proofreading and Repairing DNA
The accuracy is DNA replication is not only due to the specificity of base-pairing
DNA polymerases also proofread each nucleotide against its template as it is covalently bonded to the growing strand
If DNA pol. finds an incorrect base, it stops, and replaces it, like deleting a letter and correctly spelling a word
f a nucleotide evades proofreading by DNA pol. Other enzymes remove and replace it. This process is called
mismatch repair
DNA molecules are constantly subjected to potentially harmful chemical and physical agents, such as X-ray
Mutations are permanent changes to the DNA sequence
Mutation:
a change in the nucleotide sequence of an organism’s DNA or in the DNA or RNA of a virus
Point Mutations
changes in a single nucleotide pair of a gene
Types of Small-scale Mutations
Substitutions
nucleotide pair substitution
is the replacement of one nucleotide and its partner with another pair of nucleotides.
silent
missense mutation
Insertions and Deletions :
Nuclease enzymes
are DNA-cutting enzymes which cut DNA at points where it may be damaged. DNA pol. Fills in the missing nucleotides and DNA ligase seals up the strand. This process is called
nucleotide excision repair
Evolutionary significant of altered DNA nucleotides
A permanent change in the DNA sequence is called a mutation
Mutations are the original source of variation on which natural selection operates during evolution and are ultimately responsible for the appearance of new species
The balance between complete fidelity of DNA replication/repair and a low mutation rate has allowed for the diversity of species
Replicating the Ends of DNA Molecules
For linear (eukaryotic) chromosomes, repeated rounds of replication produce shorter and shorter DNA molecules within uneven (“staggered”) ends
Telomeres
are regions at the ends of the chromosomes
this region does not contain any genes, and instead contains multiple repetitions of one short nucleotide sequence (in humans this is TTAGGG)
telomeres have an important protective function:
they serve as a kind of buffer zone that provides some protection against the organism’s gene shortening
but, they don’t prevent the erosion of genes near the telomeres, they only postpone it
Telomerase enzyme catalyses the lengthening of telomeres in eukaryotic germ cells, but this enzyme is not active in human somatic cells
Figure 16.15
Synthesis of the leading strand during DNA replication
1.After RNA primer is made, DNA pol III starts to synthesize the leading strand.
The leading strand is elongated continuously in the 5 ---> 3 direction as the fork progresses.
Figure 16.14
Addition of a nucleotide to a DNA strand.
DNA polymerase catalyzes the addition of a nucleotide to the 3' end of a growing DNA strand, with release of two phosphates
Figure 16.16
Synthesis of the lagging strand
Figure 16.17
The double-stranded DNA of the circular bacteria chromosome is opened at the origin of replication, forming a replication bubble. ... Proteins called single-strand binding proteins coat the separated strands of DNA near the replication fork, keeping them from coming back together into a double helix.
A chromosome consists of a DNA molecule packed together with proteins
Bacterial chromosome
: circular, small, few proteins associated with it
Eukaryotic chromosome: linear, larger, much more protein associated with it
Each eukaryotic chromosome contains a single linear DNA double helix
Histones
are the proteins responsible for the first level of packaging of DNA
Heterochromatin
is highly condensed and largely inaccessible, but euchromatin is less compact. Most chromatin is in the form of
euchromatin
, and it is this form that is accessible for transcription of genes