Module 2: Topic 1‐C The Flow of Genetic Information in the Cell

(Central Dogma of Life)

Figure 1. Flow of genetic information from DNA to RNA to Proteins showing the
(A) key enzymes involved, (B) biomolecules produced in each process,
and (C) some organisms capable of processes other than the main events
in the central dogma.
 Introduction

The flow of genetic information is from DNA to RNA to proteins (Fig. 1).
How is this made possible? Instructions for making proteins with the correct
sequence of amino acids are encoded in DNA. DNA is found in chromosomes and in
eukaryotic cells, chromosomes always remain in the nucleus, but proteins are made
at ribosomes in the cytoplasm or on the rough endoplasmic reticulum (RER). However,
it is RNA that carries the information from DNA in the nucleus (during transcription)
to a ribosome in the cytoplasm and then helps assemble the protein (translation
process). The copying of DNA to RNA is relatively straightforward, with one nucleotide
being added to the mRNA strand every nucleotide read in the DNA strand. The
translation to protein is a bit more complex because three mRNA nucleotides
correspond to one amino acid in the polypeptide sequence. However, the translation
to protein is still systematic and colinear, such that nucleotides 1 to 3 correspond to
amino acid 1, nucleotides 4 to 6 corresponds to amino acid 2, and so on (Fig. 1B).
discovering this sequence of events was a major milestone in molecular biology. It is
called central dogma of biology. These two processes: transcription (DNA encodes
RNA) and translation (RNA encodes proteins) are involved in the central dogma which
we will consider in detail later.

Topic 1 – C1 DNA REPLICATION/SYNTHESIS

This is one of the most basic processes that occurs within a cell. Each time a
cell divides, the two resulting daughter cells must contain exactly the same genetic
information, or DNA (genetic information in all cells and some viruses), as the parent
cell. To accomplish this, each strand of existing DNA acts as template for replication.
This means that during DNA replication, the parent molecules unwind, and two new
daughter strands are built based on base pairing rules (Fig. 1.1).

Figure 1.1. Overview of DNA REPLICATION 1

 Learning Outcomes

At the end of this topic, you have to:

1. Compare and contrast the activities of enzymes required for replication.

2. Describe the order of events at an origin of replication and each replication
fork.
3. Differentiate the different modes of replication.
4. Compare and contrast the leasing strand from the lagging strand.
5. Describe how the structure of telomerase enables proper replication.

Activating Prior Knowledge

Reflect on the five learning outcomes above. Complete the Table below:

Learning What do you know? Any questions/clarifications in relation

Outcomes to learning outcomes
1
2
3
4
5

Learning Activity 4.
Read the materials below while keeping in mind the learning outcomes.
While reading, be guided by the following questions and answer them after.

1. What are the similarity and differences in the DNA replication between
prokaryote and eukaryotes?
2. What are Okazaki fragments? Clearly explain why Okazaki fragments exist.
3. Why are DNA sequences be replicated with high fidelity and accuracy?

Reading Material

KEY CONCEPTS:

In all cells during Replication

• Proteins/enzymes interact with DNA in all biological activities involving DNA.
• DNA must be unwound to replicate.
• Topoisomerases catalyze changes in supercoiled state of DNA.
• DNA replication has three distinct phrases (initiation, elongation, and
termination).
• DNA replication is very accurate since it allows 1x10-8 mistakes/base.
• Mutations have several causes and involve base sequence changes.
• DNA repair corrects errors using highly evolved correction systems.

DNA Replication must be done with great accuracy and at a breakneck speed

E. coli replicates its DNA at a rate of 1000 nucleotides per second with less than
one error in a billion nucleotides
Eukaryotic replication proceeds at a rate ranging from 500 to 5000 nucleotides
per minute at each replication fork (100 nucleotides per second)
In semiconservative replication each strand of the double helix parent serves as a
template to make two new daughter complementary strands, this was demonstrated
in the experiment done by Meselson and Stahl in 1958.

Figure 1-2. Three mechanisms of DNA strand growth that are consistent
with semiconservative replication.

The third mechanism—bidirectional growth of both strands from a single origin of

replication— appears to be the most common in both eukaryotes and prokaryotes.
Replication indeed begins at an origin of replication, but that double helix then
unwinds in opposite directions, replicating DNA both ways away from the origin from
two replication fork (Fig. 1.3).
Modes of Replication
• Individual units of replication are called replicons each contains a replication
origin.

1. Theta replication
• a common type of replication that takes place in circular DNA (eg. E.coli)
2. Rolling-circle replication
• takes place in some viruses and in the F factor of E. coli
3. Linear eukaryotic replication
• Replication takes place simultaneously from thousands of origins.

Table 1. Characteristics of theta, rolling-circle and linear eukaryotic replication

Below is a list of the key replication proteins and their functions:

The Process of replication

DNA replication is a sequence of repeated condensation (dehydration synthesis)

reactions linking nucleotide monomers into a DNA polymer. Like all biological
polymerizations, replication proceeds in three enzymatically catalyzed and
coordinated steps: initiation, elongation, and termination.

A. Initiation

DNA synthesis starts at one or more origins of replication. These are DNA
sequences targeted by initiator proteins in E. coli (Fig. 1.3). Sequences at replication
origins that bind to initiation proteins tend to be rich in adenine and thymine bases.
This is because A‐T base pairs have two hydrogen (H‐) bonds that require less energy
to break than the three H‐bonds holding G‐C pairs together.
Figure 1.3A. Origin of replication in E. coli. Replication initiates at a unique site on
the E. coli chromosome, designated the origin (ori).

Figure 1.3B. Replication origins in eukaryotic chromosomes. Replication initiates at

multiple origins (ori), each of which produces two replication forks.
 Replicon – region of DNA served by one replication origin.

Three Common Features of Replication Origins

1. Replication origins are unique DNA segments that contain multiple short
repeated sequences.
2. These short repeat units are recognized by multimeric origin-binding proteins.
3. Origin regions usually contain an AT-rich stretch

*Origin-binding proteins control the initiation of DNA replication by directing assembly

of the replication machinery to specific sites on the DNA chromosome.

Three types of replication origins:

1. E. coli oriC
2. Yeast autonomously replicating sequences (ARS)
3. Simian virus 40 (SV40) origin

Initiation proteins recognize and begin unwinding the double helix by bending E. coli
DNA at the ori. Helicase then continues to unwind the DNA. SSBs (single stranded
binding proteins) stabilize unwound DNA. DNA unwinding creates replicating bubbles,
or replicons, with replication forks at either end. Unwinding circular DNA molecule
(or any double helix that is rigidly associated with chromosomal proteins whenever it
is not replicating) causes the DNA to twist and coil on itself, a phenomenon called
supercoiling. If not relieved, this strain would quickly break the covalent bonds along
DNA, but this strain is relieved by the enzyme topoisomerase.

Making a new DNA strand starts with making an RNA primer with RNA nucleotides and
primase enzymes (Fig. 1.4).

B. Elongation
In this phase, DNA nucleotides are then added to the 3’ ends of primers by a DNA
polymerase (DNA pol). All DNA polymerases so far discovered can only elongate a pre-
existing DNA or RNA strand, the primer since this DNA pol particularly DNA polymerase
III (DNA Pol III) cannot initiate chains.

The two strands in the DNA duplex are opposite or antiparallel (5′→ 3’ and 3’→
5’) in chemical polarity, but all DNA polymerases catalyze nucleotide addition at the 3’-
hydroxyl ends of a growing chain, so the new strand can grow only in the 5′→ 3’
direction (Fig. 1.5) 5’′→ 3’. With this in mind, let’s examine one of the two replication
forks in a bubble (Fig. 1.3). Along one template strand, DNA polymerase III can
synthesize a complementary strand continuously by elongating the new DNA strand 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 leading
strand. Only one primer is required for DNA pol III to synthesize the leading strand
(see Fig. 1.6). To elongate the other new strand of DNA in the mandatory 5′→ 3’
direction, DNA pol III must work along the other template strand in the direction away
from the replication fork. The DNA strand elongate the lagging strand in the direction
away from the replication fork. The DNA strand elongating in this direction is called
the lagging strand. However, DNA pol III can still elongate the lagging strand or make
fragments in a 5′→ 3’direction because this template lagging strand forms a
“trombone structure” allowing the enzyme to add new nucleotides at the 3’hydroxyl
end of a growing segment. In contrast to the leading strand, which elongates
continuously, the lagging strand is synthesized discountinuously, as a series of
segments or fragments. These segments of the lagging strand are called Okazaki
fragments, after the Japanese scientist who discovered them. The fragments are
about 1,000-2,000 nucleotides long in E. coli and 100-200 nucleotides long in
eukaryotes. Synthesis of the leading strand and synthesis of the lagging strand occur
concurrently and at the same rate.
 Figure 1.4. Priming and directionality problems resulting from the structure of DNA
and the properties of DNA polymerases.

A)

Figure 1.6. Synthesis of the leading strand and lagging strand during DNA replication.
DNA Polymerases Catalyze Replication

DNA polymerase
• The enzyme that is responsible for the polymerization of nucleotides to nucleic
acid (DNA) during the elongation phase of DNA replication.
•
The first DNA polymerase enzyme was discovered in E. coli by Arthur Kornberg, for
which he received the 1959 Nobel Prize in Chemistry. The 1 st DNA polymerase
discovered was DNA pol I.
E. coli DNA Pol I has 3 enzymatic activities:
1. Polymerization 5’ 3’
2. Exonuclease 3’ 5’ (Proofreading)
3. Exonuclease 5’ 3’ (Edit out sections of damaged DNA)

It was Thomas Kornberg, one of Arthur Kornberg’s sons, who later found two
more faster‐acting DNA polymerases (DNA Pol II and DNA Pol III).
• Pol I and II – known as main DNA repair enzymes
• Pol III – known as the main DNA replication enzyme (see Table)

DNA pol III is highly “processive” while DNA Pol I is “distributive”.

Processivity is continuous synthesis by polymerase without dissociation

from the template. (It can be observed in the leading template strand)

• A DNA polymerase that is Distributive will dissociate from the template

after each nucleotide addition. (It can be observed in the lagging template
strand).

• DNA polymerase Error rate = 1/109 bp = 1x109 in the cell which is 100-1000x
better than RNA polymerase (main enzyme use during transcription).

Table 3. Characteristics of DNA Polymerase in E. coli

Although DNA polymerases replicate DNA with high fidelity with as little as one error
per 107 nucleotides, mistakes do occur and during the replication, DNA polymerases
proofread each nucleotide against its template as soon as it is added to the growing
strand. The polymerase can sense a mismatched base pair, slow down and then
catalyze repeated hydrolyses of nucleotides. Upon finding an incorrectly paired
nucleotide, the polymerase removes the nucleotide and then resumes synthesis. (This
action is similar to fixing a typing error by deleting the wrong letter and then entering
the correct letter.) Fig. 1.7 (below) illustrates this basic proofreading by DNA
polymerase

Fig. 1.7. Detection of replication errors and correction by DNA polymerase

proofreading.
C. Termination

In prokaryotes, replication is complete when two replication forks meet after

replicating their portion of the circular DNA molecule (Fig. 1.8). In eukaryotes, many
replicons fuse to become larger replicons, eventually reaching the ends of the
chromosomes. And now… there is still another problem, illustrated below in Fig. 1.9.

1. In prokaryotes
• Pol I cleaves off RNA primers and fills in gaps (both leading and lagging
strands); as well as RNase H (bacteria)
• DNA ligase seals gaps or nicks

Figure 1.8. Plasmid DNA replication

2. In Eukaryotes
• Linear chromosomes (ie, DNA molecules) have a unique problem replicating
their ends or telomeres
The problem – it’s a linear chromosome, so how to complete the
ends? (can’t just ligate ends and get a circle as with E. coli
chromosome)
• Ends of linear DNA will be shortened with each round of replication as it
will form a gap once primer is removed
• Therefore, chromosomal end must be repaired
• The enzyme telomerase prevents progressive shortening of lagging strands
during eukaryotic DNA replication
Telomerase is an RNA directed DNA polymerase, containing RNA
template. (Thus, it is a ribonucleoprotein).
The protein component of telomerase is a reverse transcriptase an
enzyme that can make DNA copies from RNA templates.

As you’ve learned, the enzyme DNA pol can add nucleotides only in the 5’to 3’
direction. In the leading strand, synthesis continues until the end of the chromosome
is reached. On the lagging strand, DNA is synthesized in short stretches, each of which
is initiated by a separate primer. When the replication fork reaches the end of the
linear chromosome, there is no place for a primer to be made for the DNA fragment
to be copied at the end of the chromosome. These ends thus remain unpaired, and
over time these ends may get progressively shorter as cells continue to divide (Figure.
1.9).
The ends of the linear chromosomes are known as telomeres, which have
repetitive sequences that code for no particular gene. In a way, these telomeres
protect the genes from getting deleted as cells continue to divide. In humans, a six
base pair sequence, TTAGGG, is repeated 100 to 1000 times. The discovery of the
enzyme telomerase (Figure 1.10) helped in the understanding of how chromosome
ends are maintained. The telomerase enzyme contains a catalytic part and a built‐in
RNA template. It attaches to the end of the chromosome, and complementary bases
to the RNA template are added on the 3′ end of the DNA strand. Once the 3′ end of
the lagging strand template is sufficiently elongated, DNA polymerase can add the
nucleotides complementary to the ends of the chromosomes. Thus, the ends of the
chromosomes are replicated.

Figure 1.9. Telomeres in the lagging strand during replication

Figure 1.10. The ends of linear chromosomes are maintained by the action of the
telomerase enzyme.

Telomerase is typically active in germ cells and adult stem cells. It is not active in
adult somatic cells. For her discovery of telomerase and its action, Elizabeth
Blackburn received the Nobel Prize for Medicine and Physiology in 2009.

Telomerase and Aging

Cells that undergo cell division continue to have their telomeres shortened
because most somatic cells do not make telomerase. This essentially means that
telomere shortening is associated with aging. With the advent of modern medicine,
preventative health care, and healthier lifestyles, the human life span has increased,
and there is an increasing demand for people to look younger and have a better quality
of life as they grow older.

In 2010, scientists found that telomerase can reverse some age‐related conditions in
mice. This may have potential in regenerative medicine.[1] Telomerase‐deficient
mice were used in these studies; these mice have tissue atrophy, stem cell depletion,
organ system failure, and impaired tissue injury responses. Telomerase reactivation
in these mice caused extension of telomeres, reduced DNA damage, reversed
neurodegeneration, and improved the function of the testes, spleen, and intestines.
Thus, telomere reactivation may have potential for treating age‐related diseases in
humans.

Cancer is characterized by uncontrolled cell division of abnormal cells. The cells

accumulate mutations, proliferate uncontrollably, and can migrate to different parts
of the body through a process called metastasis. Scientists have observed that
cancerous cells have considerably shortened telomeres, and that telomerase is active
in these cells. Interestingly, only after the telomeres were shortened in the cancer
cells did the telomerase become active. If the action of telomerase in these cells can
be inhibited by drugs during cancer therapy, then the cancerous cells could potentially
be stopped from further division.

DNA REPAIR

As with any complex process with many moving parts, replication is error prone.
Therefore, we will also look at how the overall fidelity of replication relies on
mechanisms of DNA repair that target specific kinds of replication mistakes, i.e.,
mutations.

Fidelity of DNA replication can be traced to three distinct activities:

1. Accurate selection of nucleotides
2. Immediate proofreading
3. Post replicative mismatch repair

To maintain the integrity of their integrity of their genomes, cells have therefore had
to evolve mechanisms to repair damaged DNA. The recent publication of the human
genome has already revealed 130 genes whose products participate in DNA repair,
more will probably be identified soon.

A failure to repair DNA produces a mutation.

Types of DNA Damage or Lesion

1. All four of the bases in DNA (A, T, C,G) can be covalently modified at various
positions.
• One of the most frequent is the loss of an amino group (deamination) –
resulting, for example, in a C being converted to a U.
2. Mismatches of the normal bases because of a failure of proofreading during DNA
replication.
• Common example: incorporation of the pyrimidine U (normally found only
in RNA) instead of T.
3. Breaks in backbone
• Can be limited to one of the two strands ( a single stranded break, SSBB) or
• On both strands (a double stranded break (DSB)
• Ionizing radiation is a frequent cause, but some chemicals produce breaks
as well.
4. Crosslinks Covalent linkages can be form between bases
• On the same DNA strand (“intrastrand”) or
• On the opposite strand (“interstrand”).
•
Several chemotherapeutic drugs used against cancers crosslink DNA
Agents that Damage DNA

• Certain wavelengths of radiation

o Ionizing radiation such as gamma rays and x-rays
o Ultraviolet rays, especially the UV-V rays (~260nm) that are absorbed strongly
by DNA but also the longer-wavelength UV-B that penetrates the ozone shield

• Highly-reactive oxygen radicals produced during normal cellular respiration as

well as by other biochelical pathways.

• Chemicals in the environment

o Many hydrocarbons, including some found in cigarette smoke
o Some plant and microbial products, e.g. the aflatoxins produced in moldy
peanuts

• Chemicals used in chemotherapy, especially chemotherapy of cancers.

General Types of DNA Damage

1. Induced – caused by external factors or substances (Fig. 1.11)

2. Spontaneous – not by external factors but within natural cell processes during
replication.

Figure 1.11. Examples of DNA damage induced by radiation and chemicals. (A) UV light
induces the formation of pyrimidine dimers, in which two adjacent pyrimidines)
e.g., thymines) are joined by cyclobutene ring structure. (B) Alkylation is the
addition of methyl or ethyl groups to various positions on the DNA bases. In this
example, alkylation of the O6 position of guanine results in formation of O6-
methylguanine. (C) Many carcinogens) e.g., benzo-(a)pyrene) react with DNA
bases, resulting in the addition of large bulky chemical groups to the DNA
molecule.
Figure 1.12. Spontaneous damage to DNA. There are two major forms of spontaneous
DNA damage: (A) deamination of adenine, cytosine, and guanine, and (B)
depurination (loss of purine bases) resulting from cleavage of the bond between
the purine bases and deoxyribose, leaving an apurinic (AP) site in DNA. dGMP =
deoxyguanosine monophosphate.
The mechanisms of DNA repair can be divided into two general classes:

1. Direct reversal of the chemical reaction responsible for DNA damage, and
(Fig. 1.13)
2. Excision repair removal of the damage’s bases followed by their replacement
with newly synthesized DNA (Fig. 1.14)

Three types of excision repair

1. Base-excision repair (BER)
2. Nucleotide-excision repair (NER)
3. Mismatch repair (MMR)

Direct chemical reversal of DNA damage

This strategy is selectively employed for the rapid removal of certain highly
mutagenic or cytotoxic lesions. For example, the alkylation lesion of O6-
methylguanine has its methyl group removed by direct transfer to a cysteine residue
in the repair protein itself, which is destroyed in the reaction.
 Figure. 1.13. Repair of O6-
methylguanine. O6-methylguanine
methyltransferase transfers the
methyl group from O 6-
methylguanine to a cysteine residue
in the enzyme’s active site.

Figure 1.13. Comparison of two major DNA repair pathways.

(A) Base excision repair

This pathway starts with a DNA glycosylase. Here, the enzyme uracil DNA
glycosylase removes an accidentally deaminated cytosine in DNA. After the
action of this glycosylase (or another DNA glycosylate that recognizes a
different kind of damage), the sugar phosphate with the missing base is cut out
by the sequential action of AP endonuclease and a phosphodiesterase. (These
 same enzymes begin the repair of depurinated sites directly.) The gap of a
single nucleotide is then filled by DNA polymerase and DNA ligase. The net
result is that the U that was created by accidental deamination is restored to
a C. AP endonuclease is so named because it recognizes any site in the DNA
helix that contains a deoxyribose sugar with a missing base; such sites can arise
either by the loss of a purine (apurinic sites) or by the loss of a pyrimidine
(apryrimidinic sites).

(B) Nucleotide excision repair

In bacteria, after a multienzyme complex has recognized a lesion such as a

pyrimidine dimer (see Figure 1.11and 1.13), one cut is made on each side of the
lesion, and an associated DNA helicase then removes the entire portion of the
damaged strand. The excision repair machinery in bacteria leaves the gap of 12
nucleotides shown. In humans, once the damaged DNA is recognized, a helicase
is recruited to unwind the DNA duplex locally. Next, the excision nuclease enters
and cleaves on either side of the damage, leaving a gap of about 30 nucleotides.
The large gap produced in the DNA helix is then repaired by DNA polymerase and
DNA ligase The nucleotide excision repair machinery in both bacteria and humans
can recognize and repair many different types of DNA damage.

This pathway detects bases that have been modified with bulky chemical
groups, like the ones that get attached to your DNA when it's exposed to
chemicals in cigarette smoke. This is also used to fix some types of
damage caused by UV radiation, for instance, when you get a sunburn. UV
radiation can make cytosine and thymine bases react with neighboring
bases that are also Cs or Ts, forming bonds that distort the double helix
and cause errors in DNA replication

(C) Mismatch Repair

This is another mechanism by the cell for dealing with mistakes that slip
by proofreading during replication.

The mismatch repair system:

Scans newly made DNA to see if there are any mispaired bases (e.g., a G
paired to a T)
Finds mismatches, cuts out the region of the mismatch. (In bacteria the
mismatched strand is recognized by the fact that it is not methylated) (Fig
5.25) as well as that of mammalian cell (Fig.5.26).
The gap created by the excision of the mismatch is then filled in correctly

(D) Double‐stranded break repair

Two major pathways, non‐homologous end joining and homologous

recombination (Fig. 5.53), are used to repair double‐stranded breaks in
DNA (that is, when an entire chromosome splits into two pieces)

Some types of environmental factors, such as high‐energy radiation, can

cause double‐stranded breaks in DNA (splitting a chromosome in two). This
is the kind of DNA damage which is caused by disasters like Chernobyl.

Double‐stranded breaks are dangerous because large segments of

chromosomes, and the hundreds of genes they contain, may be lost if the
break is not repaired.

In non-homologous end joining, the two broken ends of the chromosomes

are simply glued back together, this repair mechanism is “messy” and
typically involves the loss, or sometimes addition, of a few nucleotides at
the cut site. So, non-homologous end joining tends to produce a mutation,
but this is better than the alternative (loss of an entire chromosome arm).

In homologous recombination, information from the homologous

chromosome that matches the damaged one (or from a sister chromatid,
if the DNA has been copied) is used to repair the break. In this process,
the two homologous chromosomes come together, and the undamaged
region of the homologue or chromatid is used as a template to replace the
damaged region of the broken chromosome. Homologous recombination is
“cleaner” than non-homologous end joining and does not usually cause
mutations.
A B

Figure 1.14. Mismatch repair (A) E. coli and (B) mammalian cells.

Figure 5-53. Two different types of end-joining for repairing double-strand breaks. (A)
Nonhomologous end-joining alters the original DNA sequence when repairing broken
chromosomes. These alterations can be either deletions (as shown) or short insertions.
(B) Homologous end-joining is more difficult to accomplish, but is much more precise.

Recent studies of the consequences of a diminished capacity for DNA

repair in humans have linked many human diseases with decreased repair
(Table 5). Thus, we saw previously that defects in a human gene whose
product normally functions to repair the mismatched base pairs resulting
from DNA replication errors can lead to an inherited predisposition to
cancers of the colon and some other organs, reflecting an increased
mutation rate.
Assessment Activity
This is a major assessment activity that requires you to do the following:

1. Group yourselves into three.

2. The group should be able to outline and discuss completely what was
happening during DNA replication.

3. The group must support their discussion/learnings by making a 3D

model of the process. They must show this while discussing or
presenting as sort of visual aid.

4. The group must be able to discuss and share their learnings on this
topic by making a vlog or video. Make sure that everyone was able to
engage and talk n the group during your brain storming and sharing.

5. Agree on the group how you are going to divide the topic and
coordinate so you can come up with the whole process involving the
three members in one presentation.

6. You will be graded as a group. The group will be graded according to

completeness of the process, accuracy of the process discusses,
organization and order of the discussion in relation to the process, the
accuracy, creativity and neatness of the model made and how it was
used during the presentation.
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https://courses.lumenlearning.com/sanjacinto‐biology1/chapter/

https://www.khanacademy.org/science/high‐school‐biology/hs‐molecular‐
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http://www.phschool.com/science/biology_place/biocoach/dnarep/

1 Jaskelioff et al., “Telomerase reactivation reverses tissue degeneration in aged

telomerase‐ deficient mice,” Nature 469 (2011): 102–7.

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