The central dogma of molecular biology

THE CENTRAL DOGMA OF MOLECULAR BIOLOGY
Jony Mallik
Industrial Pharmacist
E-mail: jonymallik@ymail.com
INTRODUCTORY PRINCIPLE
Biomolecules are the molecules that are synthesized within living organism and perform different
functions in that organism in terms of separate metabolic & biosynthetic purposes. The
biomolecules could be a coarse one like- polypeptides, polysaccharides, lipids or any other
macromolecules. Protein is the only biomolecule which is synthesized depending on body
individual need & participate in different biologic signaling system like plasma protein, membrane
protein, receptor protein, enzyme protein system. Proteins are the essential tools for proper growth
& repair of muscle. Some proteins, people may easily get from food stuff but, some are very
authentic & body usually biosynthesized that types of protein.
➢ In vivo protein synthesis and its phenomenon is the central dogma of molecular biology.
➢ Central dogma of molecular biology is the explanation of two different steps required in
synthesizing a protein.
➢ Central dogma deals with the details of genetic information (DNA) transformation to m
RNA & then to a protein.
➢ The two vulnerable steps of protein synthesis are-
✓ Transcription
✓ Translation

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Deoxyribonucleic acid (DNA)
DNA is the molecule of life & a very essential nucleic acid located at the chromosome of cellular
nucleus. All the genetic information is stored in DNA molecule & transformed into mRNA
(Transcription) then to a protein (Translation), that is why DNA is sometimes said as “The Reserve
Bank of Genetic Information”.
✓ In DNA there are four bases: adenine (A), guanine (G), thymine (T) and cytosine (C).
Adenine and guanine are purines; thymine and cytosine are pyrimidines.

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✓ A nucleoside is a pyrimidine or purine base covalently bonded to a sugar. In DNA, the
sugar is deoxyribose and so this is a deoxynucleoside. There are four types of
deoxynucleoside in DNA; deoxyadenosine, deoxyguanosine, deoxythymidine and
deoxycytidine.
✓ A nucleotide is base + sugar + phosphate covalently bonded together. In DNA, where the
sugar is deoxyribose, this unit is a deoxynucleotide.
✓ In DNA the nucleotides are covalently joined together by 3’5’phosphodiester bonds to
form a repetitive sugar–phosphate chain which is the backbone to which the bases are
attached.
✓ The DNA sequence is the sequence of A, C, G and T along the DNA molecule which
carries the genetic information.
✓ In a DNA double helix, the two strands of DNA are wound round each other with the bases
on the inside and the sugar–phosphate backbones on the outside. The two DNA chains are
held together by hydrogen bonds between pairs of bases; adenine (A) always pairs with
thymine (T) and guanine (G) always pairs with cytosine (C)

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DNA Replication
DNA replication is the process of the genesis of two identical replica of the parent DNA molecule
under the agency of some sorts of enzyme. Newly formed molecule contains same genetic
information that the parent molecule may have. Replication process involve numerous complicated
task. All the new molecule further participate in transcription process.
Enzymes & Protein that play a key role in DNA replication process are-
❖ DNA polymerase I & III
❖ DNA primase
❖ DNA gyrase & nuclease
❖ DNA helicase
❖ DNA ligase
❖ Single stranded DNA binding protein (SSB)
DNA Replication models
The process of DNA Replication was hiding many secrets. One of the most important was how
the two daughter strands are created. As we have noticed in previous chapters of our site the DNA
is a complex of two chains! In order the hereditary phenomenon to be explained, these strands
should be accurately copied and transmitted from the parental cell to the daughter ones. These are
three possible models that describe the accurate creation of the daughter chains:
Semiconservative Replication According to this model, DNA Replication would create two
molecules. Each of them would be a complex of an old (parental and a daughter strand).

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Conservative Replication According to this model, the DNA Replication process would create a
brand new DNA double helix made of two daughter strands while the parental chains would stay
together.
Dispersive Replication According to this model the Replication Process would create two DNA
double-chains, each of them with parts of both parent and daughter molecules.
Replication Process
The overall DNA replication process is very complicated job and involves a set of proteins and
enzymes that collectively assemble nucleotides in the predetermined sequence. A particular
replication process is consists of following distinct steps to form two identical replica.
INITIATION
►The site from which the replication starts are called Replication origin or Origin of
replication. In order for DNA replication to begin, the double stranded DNA helix must
open, for that both of the helicase & SSB protein bind to that region to unwind the helix &
stabilize the DNA into two strand.
►
The open portion of parent DNA are referred as “ Replication fork”, which is asymmetrical
as the two single strands run in a anti-parallel direction.
PRIMER SYNTHESIS
►The synthesis of a new, complementary strand of DNA using the existing strand as a
template is brought about by enzymes known as DNA polymerases. In addition to
replication they also play an important role in DNA repair and recombination.
►
One of the most important steps of DNA Replication is the binding of RNA Primase in
the initiation point of the 3'-5' parent chain. RNA Primase can attract RNA nucleotides
which bind to the DNA nucleotides of the 3'-5' strand due to the hydrogen bonds between
the bases. RNA nucleotides are the primers (starters) for the binding of DNA nucleotides.

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SYNTHESIS OF LEADING STRAND
►
Then DNA polymerase III play its role in initiating the leading strand which required few
steps & therefore is synthesized quickest.
►
DNA polymerase III (DNA pol III) recognizes the 3' OH end of the RNA primer, and adds
new complementary nucleotides. As the replication fork progresses, new nucleotides are
added in a continuous manner, thus generating the new strand.
SYNTHESIS OF LAGGING STRAND
►
DNA is synthesized in a discontinuous manner by generating a series small fragments of
new DNA in the 5' →
3' direction. These fragments are called Okazaki fragments, which are
later joined to form a continuous chain of nucleotides. This strand is known as the lagging
strand since the process of DNA synthesis on this strand proceeds at a lower rate.
LIGATION & TERMINATION
►
After primer removal is completed the lagging strand still contains gaps or nicks between
the adjacent Okazaki fragments. The enzyme ligase identifies and seals these nicks by
creating a phosphodiester bond between the 5' phosphate and 3' hydroxyl groups of
adjacent fragments.
►This replication machinery halts at specific termination sites which comprise a unique
nucleotide sequence. This sequence is identified by specialized proteins called tus which
bind onto these sites, thus physically blocking the path of helicase. When helicase
encounters the thus protein it falls off along with the nearby single-strand binding
proteins.

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DIAGRAMMATIC SEQUENCES OF DNA REPLICATION
Initiation
Primer synthesis

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Synthesis of leading strand
Synthesis of lagging strand

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Termination
TRANSCRIPTION
Transcription is the preliminary step of the gene expression that deals with the details of the
synthesis on mRNA (messenger RNA) from the promoter gene on the DNA molecule under the
agency of some enzymes & transcription factors. The enzymes involved in transcription are called
RNA polymerases. Prokaryotes have one type; eukaryotes have three types of nuclear RNA
polymerases.
RNA Synthesis
There are a number of different types of RNA, which play different roles in the cell:
♦ mRNA - encodes proteins.
♦ rRNA - forms the ribosome, including the active site for peptide bond formation.
♦ tRNA - adaptor, binds amino acids and rRNA and translates between mRNA and protein.
♦ snRNA - small nuclear RNA, forms snRNPs, which process mRNA by removing introns.

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♦ snoRNA - small nucleolar RNA, forms snoRNPs, which process rRNA, mostly by methylation
and isomerisation.
♦ si RNA - small interfering RNA, involved in gene silencing and regulation.
♦ gRNA - guide RNA, needed for RNA editing, the removal and insertion of bases into mRNA
♦ hnRNA - rag-bag of unprocessed pre-mRNA transcripts and other heterogeneous nuclear RN As
of less well defined function.
RNA polymerase
►RNA polymerase is the enzyme that generates RNA from DNA. Cells contain 20 times
more RNA than DNA: in fact, about 5% of the cell is RNA, although only 5% of this 5% is
mRNA, because most of the RNA in the cell is rRNA.
►
Since the majority of RNA is rRNA, Significantly more RNA is transcribed than translated.
This is especially true in eukaryotes, whose mRNA requires processing to remove introns.
►
The primary gene products of RNA polymerase (in eukaryotes) are:
• (pre-) mRNA (messenger);
• rRNA (ribosomal);
• tRNA (transfer);
• snRNA (small nuclear - spliceosomes);
• Other hnRNA (heterogeneous nuclear, such as snoRNA – small nucleolar).
Eukaryotic RNA Polymerases
Eukaryotes have three RNA polymerases which synthesized different type of RNA
❖ RNA polymerase I - rRNA.
❖ RNA polymerase II - mRNA.
❖ RNA polymerase III - tRNA
Steps Involve in Transcription of DNA to mRNA -

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The overall transcription process required three distinct steps to complete-
➢ Initiation
➢ Elongation
➢ Termination
Initiation
✓ Transcription actually starts from a very special region of DNA double helix called
“Promoter Region”, a region which has meaningful nucleobase sequences of gene product
(Protein).
✓ RNA polymerase with transcription factor (sigma factor) associates to the promoter region
to initiate transcription
Promoters
1. Only one strand of the DNA that encodes a promoter, a regulatory sequence, or a gene needs to
be written.
2. The strand that is written is the one that is identical to the RNA transcript, thus the antisense
strand of the DNA is always selected for presentation.
3. The first base on the DNA where transcription actually starts is labeled +1.
4. Sequences that precede, are upstream of the first base of the transcript, are labeled with negative
numbers. Sequences that follow the first base of the transcript, are downstream, are labeled with
positive numbers.

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Steps of Transcription Process
Elongation
✓ RNA polymerase starst to move forward in a 5' to 3' direction. The polymerase induces the
3' hydroxyl group of the nucleotide at the 3' end of the growing RNA chain which attacks
(nucleophilic) a phosphorous of the incoming ribonucleotide.
✓ The complementary sequence of DNA come out as pre-mRNA during movement of RNA
polymerase
Termination
✓ The mechanisms by which eukaryotes terminate transcription are poorly understood. Most
eukaryotic genes are transcribed for upto several thousand base pairs beyond the actual end
of the gene. The excess RNA is then cleaved from the transcript when the RNA is processed
into its mature form.
✓ Finally the sigma factor & RNA polymerase remains separate as intact form.

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Processing of RNA/ RNA splicing
The newly synthesized pre-mRNA contains “exon” & “intron” segment within it, where the
intron part has no impact on protein synthesis hence, a further processing need to remove intron &
make it as pure & mature m RNA. The process of cutting & removing introns from pre-mRNA &
joining the exons is referred as “RNA splicing”
RNA processing
Mechanism of RNA processing / splicing
The mechanism of RNA splicing is very complicated. The biochemical mechanism of splicing
consists of two reactions-
First Reaction
In order to start the first reaction, the ending nucleotide of the intron react to first nucleotide to
form intron lariat, which will be remove at second reaction.

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Second Reaction
Formed intron lariat then cut & removed from the pre-mRNA & exons are joined together to form
the mature or spliced RNA.
Mechanism of RNA splicing
TRANSLATION
Translation is a very key portion of central dogma, that deals with the synthesis of gene product
(protein) form spliced mRNA by using tRNA, ribosomal subunit & some factors.
Steps Involve in Translation of mRNA to Protein
The overall mechanism of protein synthesis in eukaryotes is basically the same as in prokaryotes,
with three phases defined as initiation, elongation and termination. However, there are some
significant differences, particularly during initiation. Translation of mRNA into a protein requires
ribosomes, mRNA, tRNA, exogenous protein factors and energy in the form of ATP and GTP.

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Initiation
✓ Four major steps are required to initiate translation: ribosome dissociation, formation of a
pre-initiation complex, formation of the 405 initiation complex and formation of the 805
initiation complex.
✓ The first step is the formation of a pre-initiation complex consisting of the 40S small
ribosomal subunit, Met-tRNAi met, eIF-2 and GTP;
✓ The pre-initiation complex now binds to the 5’ end of the eukaryotic mRNA, a step that
requires eIF-4F (also called cap binding complex) and eIF-3.
✓ The complex now moves along the mRNA in a 5’ to 3’ direction until it locates the AUG
initiation codon.
✓ Once the complex is positioned over the initiation codon, the 60S large ribosomal subunit
binds to form an 80S initiation complex, a step that requires the hydrolysis of GTP and
leads to the release of several initiation factors.
Elongation
✓ The elongation stage of translation in eukaryotes requires three elongation factors, eEF-
1A, eEF-IB and eEF-2, which have similar functions to their prokaryotic counterparts EF-
Tu, EF-Ts and EF-G.
✓ Although most codons encode the same amino acids in both prokaryotes and eukaryotes,
the mRNAs synthesized within the organelles of some eukaryotes use a variant of the
genetic code.
✓ During elongation the protein is synthesized one amino acid at a time on the 80S ribosome.
This process occurs in three major steps: binding of charged tRNA, peptide bond
formation, translocation of the growing peptide chain.

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Termination
✓ When a stop codon appears at the A site translation is terminated. There are no tRNA's that
recognize stop codons.
✓ Instead releasing factors, eRF, recognize the stop codon. The releasing factors along with
peptidyl transferases and GTP catalyze the hydrolysis of the bond between the polypeptide
chain and the tRNA.
✓ The protein and tRNA disassociate from the P site and the ribosome dissociates into the
405 and 605 subunits releasing the mRNA.
Diagrammatic sequence of Protein synthesis

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References
1) David Hames., Niger Hooper., Biochemistry- 3rd edition.
2) Jeremy M. Berg.,John L. Tymoczko., Lubert Stryer. Biochemistry-5th edition.
3) Robert K. Murray., Daryl K. Granner., Peter A. Mayes., Victor W. Rodwell., Harper’s
Illustrated Biochemistry- 22nd edition.
4) H.P.Gajera., S.V.Patel., Fundamentals of Biochemistry-A Textbook- 1st edition (2008).
5) www.google.com (Wikipedia)
THE END

The central dogma of molecular biology

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