DNA repair is a collection of processes cells use to identify and correct damage to DNA molecules. Around 1 million lesions can occur per cell per day due to normal metabolic activities and environmental factors like UV light. Unrepaired lesions can alter gene transcription or cause mutations. The main types of DNA repair are direct reversal, base excision repair, nucleotide excision repair, and double-strand break repair. Cells have checkpoint mechanisms to detect DNA damage and initiate repair or induce apoptosis if damage is too severe. Defects in DNA repair can cause diseases like xeroderma pigmentosum or increase cancer risks. Telomere shortening due to factors like oxidation also contributes to cellular aging, and telomerase may help counter this
Mismatch Repair Mechanism Is One Of The Important DNA Repair Mechanism Which Recognizes And Replaces The Wrong Nucleotides. DNA Repair Is Important Since Its Failure Leads To Deadly Diseases Like Cancer. In This Presentation, You Will Learn About DNA Repair, Mismatch Repair, Proteins Involved In Prokaryotic And Eukaryotic MMR, Diagrams, Biological Importance Of MMR And References For Further Study.
SOS repair
a system that repairs severely damaged bases in DNA by base excision and replacement, even if there is no template to guide base selection. This process is a last resort for repair and is often the cause of mutations.
One of the first plausible models to account for the preceding observations was
formulated by Robin Holliday.
The key features of the Holliday model are the formation of heteroduplex DNA; the
creation of a cross bridge; its migration along the two heteroduplex strands,
termed branch migration; the occurrence of mismatch repair; and the
subsequent resolution, or splicing, of the intermediate structure to yield different
typesof recombinant molecules.
Mismatch Repair Mechanism Is One Of The Important DNA Repair Mechanism Which Recognizes And Replaces The Wrong Nucleotides. DNA Repair Is Important Since Its Failure Leads To Deadly Diseases Like Cancer. In This Presentation, You Will Learn About DNA Repair, Mismatch Repair, Proteins Involved In Prokaryotic And Eukaryotic MMR, Diagrams, Biological Importance Of MMR And References For Further Study.
SOS repair
a system that repairs severely damaged bases in DNA by base excision and replacement, even if there is no template to guide base selection. This process is a last resort for repair and is often the cause of mutations.
One of the first plausible models to account for the preceding observations was
formulated by Robin Holliday.
The key features of the Holliday model are the formation of heteroduplex DNA; the
creation of a cross bridge; its migration along the two heteroduplex strands,
termed branch migration; the occurrence of mismatch repair; and the
subsequent resolution, or splicing, of the intermediate structure to yield different
typesof recombinant molecules.
DNA repair system lecture that were prepered by Ph.D. students Mohammed Mohsen and Aliaa Hashim at microbiology department / college of medicine / babylon university.
Each day the genome is subjected to thousands of DNA damaging events from diverse sources which can have potentially deleterious consequences. In order to maintain genome integrity eukaryotic cells have evolved a highly complex and multifaceted response network called the DNA damage response, or ?DDR?....
Each day the genome is subjected to thousands of DNA damaging events from diverse sources which can have potentially deleterious consequences. In order to maintain genome integrity eukaryotic cells have evolved a highly complex and multifaceted response network called the DNA damage response, or ?DDR?
Each day the genome is subjected to thousands of DNA damaging events from diverse sources which can have potentially deleterious consequences. In order to maintain genome integrity eukaryotic cells have evolved a highly complex and multifaceted response network called the DNA damage response, or ?DDR?....
Each day the genome is subjected to thousands of DNA damaging events from div...semualkaira
Each day the genome is subjected to thousands of DNA damaging events from diverse sources which can have potentially deleterious consequences. In order to maintain genome integrity eukaryotic cells have evolved a highly complex and multifaceted response network called the DNA damage response, or ?DDR?..
Each day the genome is subjected to thousands of DNA damaging events from diverse sources which can have potentially deleterious consequences. In order to maintain genome integrity eukaryotic cells have evolved a highly complex and multifaceted response network called the DNA damage response
SOS response was discovered by Miroslav Radman. It's a part of DNA repair system- synthesizes enzymes required for DNA repair. Cellular response to UV damage.
Describe the repair mechanisms used during DNA replication.Soluti.pdfkellenaowardstrigl34
Describe the repair mechanisms used during DNA replication.
Solution
DNA like any other molecule can undergo a variety of chemical reactions. Because DNA
uniquely serves as a permanent copy of the cell genome, however, changes in its structure are of
much greater consequence than are alterations in other cell components, i.e RNA’s and Proteins.
Mutations can consider the incorporation of incorrect bases during DNA replication. And also,
various chemical changes occur in DNA either spontaneously or as a result of exposure to
chemicals or radiation. Such damage to DNA can block replication or transcription, and can
result in a high frequency of mutations—consequences that are unacceptable from the standpoint
of cell reproduction.
To maintain the integrity of their genomes, cells have therefore had to evolve mechanisms to
repair damaged DNA. DNA repair mechanism can be divided into two general classes: (1) direct
reversal of the chemical reaction responsible for DNA damage, and (2) removal of the damaged
bases followed by their replacement with newly synthesized DNA. The rate of DNA repair is
dependent on many factors, including the cell type, the age of the cell, and the extracellular
environment. A cell that has accumulated a large amount of DNA damage, or one that no longer
effectively repairs damage incurred to its DNA, can enter one of three possible states:
1. an irreversible state of dormancy, known as senescence
2. cell suicide, also known as apoptosis or programmed cell death
3. unregulated cell division, which can lead to the formation of a tumor that is cancerous
The DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal
functionality of that organism.
Direct reversal
Cells are known to eliminate three types of damage to their DNA by chemically reversing it.
These mechanisms do not require a template,the types of damage they counteract can occur in
only one of the four bases. Such direct reversal mechanisms are specific to the type of damage
incurred and do not involve breakage of the phosphodiester backbone. The formation of
pyrimidine dimers upon irradiation with UV light results in an abnormal covalent bond between
adjacent pyrimidine bases. The photo reactivation process directly reverses this damage by the
action of the enzyme photolyase, whose activation is obligately dependent on energy absorbed
from blue/UV light (300–500 nm wavelength) to promote catalysis.
The second type of damage, methylation of guanine bases, is directly reversed by the protein
methyl guanine methyl transferase (MGMT),
The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and
adenine.
Excision Repair mechanisms
Single strand damage:
When only one of the two strands of a double helix has a defect, the other strand can be used as a
template to guide the correction of the damaged strand. In order to repair damage to one of the
two paired molecules of DNA, there exist a number of excis.
The SOS response was discovered and named by Miroslav Radman in 1975.
It's a global response to DNA damage in which the cell cycle is arrested and DNA repair and mutagenesis is induced. It’s a part of DNA repair system; synthesizes DNA repair enzymes.
MECHANISM:
1.In case of excessive DNA damage, stress conditions etc., a cell responds by activating signal or RecA protein. It floats in the vicinity of the cell in search of any damage in the DNA.
2. A RecA protein specifically binds to the single stranded DNA. On binding with the single stranded DNA fragments, RecA forms a filament-like structure around the DNA.
3.Then, a LexA repressor comes in contact with the nucleoprotein filament assembled by the RecA protein. When RecA interacts with the repressor protein, it gets converted to RecA protease.
4.The formation of RecA protease causes autocatalytic proteolysis of LexA repressor protein. Thus, a LexA protein cannot bind with the SOS operator.
5.Inactivation of LexA protein activates the inducer proteins that repair the DNA damage but alters the DNA sequence.
6.After DNA repair, the RecA protein loses its efficiency to cause proteolysis, and the LexA protein will again bind to the SOS operator or switch off the SOS system.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
This pdf is about the Schizophrenia.
For more details visit on YouTube; @SELF-EXPLANATORY;
https://www.youtube.com/channel/UCAiarMZDNhe1A3Rnpr_WkzA/videos
Thanks...!
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
WARBURG EFFECT Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970) In 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme.
WARNBURG EFFECT : cancer cells under aerobic (well-oxygenated) conditions to metabolize glucose to lactate (aerobic glycolysis) is known as the Warburg effect. Warburg made the observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
This presentation explores a brief idea about the structural and functional attributes of nucleotides, the structure and function of genetic materials along with the impact of UV rays and pH upon them.
Richard's entangled aventures in wonderlandRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Deep Behavioral Phenotyping in Systems Neuroscience for Functional Atlasing a...Ana Luísa Pinho
Functional Magnetic Resonance Imaging (fMRI) provides means to characterize brain activations in response to behavior. However, cognitive neuroscience has been limited to group-level effects referring to the performance of specific tasks. To obtain the functional profile of elementary cognitive mechanisms, the combination of brain responses to many tasks is required. Yet, to date, both structural atlases and parcellation-based activations do not fully account for cognitive function and still present several limitations. Further, they do not adapt overall to individual characteristics. In this talk, I will give an account of deep-behavioral phenotyping strategies, namely data-driven methods in large task-fMRI datasets, to optimize functional brain-data collection and improve inference of effects-of-interest related to mental processes. Key to this approach is the employment of fast multi-functional paradigms rich on features that can be well parametrized and, consequently, facilitate the creation of psycho-physiological constructs to be modelled with imaging data. Particular emphasis will be given to music stimuli when studying high-order cognitive mechanisms, due to their ecological nature and quality to enable complex behavior compounded by discrete entities. I will also discuss how deep-behavioral phenotyping and individualized models applied to neuroimaging data can better account for the subject-specific organization of domain-general cognitive systems in the human brain. Finally, the accumulation of functional brain signatures brings the possibility to clarify relationships among tasks and create a univocal link between brain systems and mental functions through: (1) the development of ontologies proposing an organization of cognitive processes; and (2) brain-network taxonomies describing functional specialization. To this end, tools to improve commensurability in cognitive science are necessary, such as public repositories, ontology-based platforms and automated meta-analysis tools. I will thus discuss some brain-atlasing resources currently under development, and their applicability in cognitive as well as clinical neuroscience.
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
2. OUTLINE
Introduction
Sources of DNA damage
Causes of DNA Damage
Mechanism of DNA repair
Global Response to DNA Damage
Medicine and DNA damage Repair
DNA repair and Cancer
DNA repair and antiaging
3. DNA REPAIR
DNA repair is a collection of processes by which a cell identifies and
corrects damage to the DNA molecules that encode its genome.
In human cells, both normal metabolic activities and environmental
factors such as UV light and radiation can cause DNA damage, resulting
in as many as 1 million individual molecular lesions per cell per day.
Many of these lesions cause structural damage to the DNA molecule and
can alter or eliminate the cell's ability to transcribe the gene that the
affected DNA encodes. Other lesions induce potentially harmful
mutations in the cell's genome, which affect the survival of its daughter
cells after it undergoes mitosis.
4. The DNA repair process is constantly active as it responds to
damage in the DNA structure.
When normal repair processes fail, and when cellular apoptosis
does not occur, irreparable DNA damage may occur, including
double-strand breaks and DNA crosslinkages.
The rate of DNA repair is dependent on many factors
the cell type,
the age of the cell
the extracellular environment.
5. DNA DAMAGE
• DNA damage is an alteration in the chemical structure of DNA, such
as a break in a strand of DNA, a base missing from the backbone of
DNA, or a chemically changed base such as 8-OHdG. Damage to
DNA that occurs naturally can result from metabolic DNA damage,
due to environmental factors and normal metabolic processes inside
the cell.
• The vast majority of DNA damage affects the primary structure of the
double helix.
6. SOURCE OF DAMAGE
DNA damage can be subdivided into two main types:
endogenous damage such as attack by reactive oxygen species produced
from normal metabolic byproducts (spontaneous mutation), especially the
process of oxidative deamination
also includes replication errors
exogenous damage caused by external agents such as
ultraviolet [UV 200-400 nm] radiation from the sun
other radiation frequencies, including x-rays and gamma rays
certain plant toxins
viruses
7. CAUSES OF DNA DAMAGE
•The most significant consequence of oxidative
stress in the body is thought to be damage to DNA.
• DNA may be modified in a variety of ways, which
can ultimately lead to mutations and genomic
instability.
• This could result in the development of a variety of
cancers including colon, breast, and prostate.
8. TYPES OF DNA DAMAGE:
Here we discuss the various types of damage to DNA, including:
oxidative damage,
hydrolytic damage,
DNA strand breaks,
and others.
9. BY RADIATION
Radiation acts by damaging DNA.
When it hurts us, it damages DNA in healthy cells
which are doing their job keeping us alive and well.
Radiation can damage DNA either by scoring a direct
hit, or by breaking-up water. The broken water is very
reactive and can cause damage to DNA (or anything else
it comes across).
10. Radiation comes in three forms, alpha, beta, and gamma.
Radiation damages DNA - cells work hard to repair it.
When we use it in medicine, e.g. in radiotherapy, it acts
by damaging DNA in cancer cells.
11.
12. BY HYDROLYSIS:
The covalent structure of DNA is unstable in aqueous solution. It
tends to hydrolyze to its monomeric components, and they
themselves are subject to various hydrolytic reactions.
A single base transformation within a DNA molecule may be
sufficient to cause a mutation, or inactivate the DNA.
Phosphodester bond and N-glycosyl bond cleavage occurs due
to hydrolysis.
14. BY OXIDATION:
• Mutations caused by oxidative DNA damage may contribute to
human disease.
• Oxidation of G generates oxoG , is highly mutagenic bcz it can
be base-pair with A as well as with C.
• if it pair with A during replication give rise G:C to T:A
transvasion cause human cancer i.e. by free radicals.
15. Cellular DNA is damaged by oxygen free radicals generated
during cellular respiration, cell injury, phagocytosis, and
exposure to environmental oxidants.
The resultant damage to DNA bases may be a significant source
of mutations that lead to cancer and other human pathology .
Because of the multiplicity of DNA modifications produced by
oxygen free radicals , it has been difficult to establish the
frequency and specificity of mutations engendered by individual
oxygen-induced DNA lesions.
18. DIRECT REVERSAL REPAIR:-
Most cases of DNA damage are not reversible. For
cases that are reversible, our body uses direct
reversal repair mechanism to correct the damaged
base.
19. MECHANISM:-
• Direct reversal repair is a mechanism of repair where the
damaged area or lesion is repaired directly by specialised
proteins in our body. It is the simplest form of DNA repair and
also, the most energy efficient method.
• It does not require a reference template unlike the other single-
strand repair mechanism.
21. EXCISION REPAIR:-
•Most such damage products involve neither pyrimidine
dimers nor O6-alkylguanine, so they must be handled by
a different mechanism. Most are removed by a process
called excision repair. The damaged DNA is first
removed, then replaced with fresh DNA.
22. MECHANISMS:-
The damaged DNA is first removed, then replaced with fresh
DNA, by one of two mechanisms:
base excision repair or
nucleotide excision repair.
Mismatch repair.
Double stranded break repair
Recombinant repair
23. BASE EXCISION REPAIR:-
Base excision repair is more prevalent and usually works on
common, relatively subtle changes to DNA bases, such as
chemical modifications caused by cellular agents.
24. MECHANISM:-
This process begins with DNA glycosylase, which extrudes a base in a
damaged base pair, then clips out the damaged base,
leaving an apurinic or apyrimidinic site that attracts the DNA repair
enzymes that remove the remaining deoxyribose phosphate and
replace it with a normal nucleotide.
In bacteria, DNA polymerase I is the enzyme that fills in the missing
nucleotide in BER;
In eukaryotes, DNA polymerase b plays this role.
However, this enzyme makes mistakes, and has no
proofreading activity.
25.
26. NUCLEOTIDE EXCISION REPAIR:-
Nucleotide excision repair generally deals with more drastic
changes to bases, many of which distort the DNA double helix.
These changes tend to be caused by mutagenic agents from
outside of the cell.
A good example of such damage is pyrimidine dimer caused
by UV light.
27. MECHANISM:-
Nucleotide excision repair typically handles bulky damage that
distorts the DNA double helix.
NER in E. coli begins when the damaged DNA is clipped by
an endonuclease on either side of the lesion, at sites 12–13 not
apart. This allows the damaged DNA to be removed as part of
the resulting 12–13-base oligonucleotide. DNA polymerase I
fills the gap and DNA ligase seals the final nick.
28.
29. MISMATCH REPAIR:-
•Mismatch repair deals with correcting mismatches of the
normal bases; that is, failures to maintain normal
Watson-Crick base pairing (A•T, C•G)
•Recognition of a mismatch requires several different
proteins.
30. - DOUBLE-STRAND BREAK REPAIR
Two method for repairing Double strand Break
By homologous recombination
By non homologous ending joints
31. BY HOMOLOGOUS RECOMBINATION
Recombinase as RecA bind to the ss-DNA
Here the broken ends are repaired using the information on the
intact sister chromatid, or on the homologous chromosome
Two of the proteins used in homologous recombination are
encoded by the genes BRCA1 and BRCA2
Accessory factors as Rad54, Rad54B, and Rdh54 help recognize
and invade the homologous region
After the formation of D-loop, DNA polymerase involved to
elongate the 3’ invading single strand
32.
33. BY NON HOMOLOGOUS ENDING
JOINTS
• Non-homologous end-joining (NHEJ) is used at other points of the cell
cycle when sister chromatids are not available for use as HR templates.
When these breaks occur, the cell has not yet replicated the region of
DNA that contains the break, so unlike the HR pathway, there is no
corresponding template strand available.
• Direct joining of the broken ends. This requires proteins that recognize
and bind to the exposed ends and bring them together for ligating. This
type of joining is also called Non homologous End-Joining (NHEJ). A
protein called Ku is essential for NHEJ
38. SOS response
SOS response causes cells to stop dividing and repair
damaged DNA.
LexA and RecA mutants always have the SOS response on.
When E. coli is exposed to agents that damage DNA, RecA
mediates proteolytic cleavage of LexA. This is induced by
RecA binding to ssDNA.
LexA is a repressor of 43 genes involved in DNA repair (all
proceeded by 20 nt sequence called the SOS box).
40. SOS Repair
E. coli Pol III is unable to replicate through lesions (AP sites,
thymine dimers), causing a replication fork “collapse”
To restore the replication fork, can either induce recombination
repair which uses a homologous chromosome as the template or
SOS repair.
Uses 2 bypass DNA polymreases (Pol IV and PolV).
These are error-prone DNA polymerases (lack the 3’ 5’
exonuclease)
SOS is a mutagenic process. This is a last resort if DNA has not
been repaired by other mechanisms.
41. CONTROL OF THE CELL
CYCLE
Three checkpoints:
The G1/S cell cycle checkpoint
G2/M DNA damage checkpoint
Mitosis checkpoint
42. G1/S CELL CYCLE CHECKPOINT
controls the passage of eukaryotic cells from the
first 'gap' phase (G1) into the DNA synthesis phase
(S).
Checks:
That the size is CORRECT
That the environment is CORRECT
43. G1/S CELL CYCLE CHECKPOINT
HOW DO THEY DO THAT?
Major proteins involved:
Cyclins (proteins) - level fluctuate in the cell cycle.
Cyclin dependent KINASES* (Cdks)
They add phosphate groups to proteins that control processes in
the cell cycle.
They only do this when the cyclins are present.
45. G2/M DNA DAMAGE CHECKPOINT
The G2/M DNA damage checkpoint prevents the cell from
entering mitosis (M phase) if the genome is damaged.
It also checks if the cell is big enough (i.e. has the resources to
undergo mitosis)
Almost exclusively, internally controlled
46. M CHECKPOINT
• The M checkpoint is where the attachment of the spindle
fibres to the centromeres is assessed.
• Only if this is correct can mitosis proceed.
• Failure to attach spindle fibres correctly would lead to
failure to separate chromosomes
48. Defects in the NER mechanism are responsible for several
genetic disorders, including:
Xeroderma pigmentosum: hypersensitivity to sunlight/UV,
resulting in increased skin cancer incidence and premature
aging
Cockayne syndrome hypersensitivity to UV and chemical
agents
Trichothiodystrophy sensitive skin, brittle hair and nails
49. .
Other DNA repair disorders include:
Werner's syndrome: premature aging and retarded growth
Bloom's syndrome: sunlight hypersensitivity, high incidence of especially leukemias
Ataxia telangiectasia sensitivity to ionizing radiation and some chemical agents
All of the above diseases are often called "segmental progerias" ("accelerated aging
diseases") because their victims appear elderly and suffer from aging-related diseases at
an abnormally young age, while not manifesting all the symptoms of old age.
Other diseases associated with reduced DNA repair function include anemia,
hereditary breast cancer and hereditary colon cancer.
50. DNA REPAIR AND CANCER
• There are at least 34 Inherited human DNA repair gene
mutations that increase cancer risk. Many of these mutations
cause DNA repair to be less effective than normal. In
particular, Hereditary nonpolyposis colorectal cancer (HNPCC)
is strongly associated with specific mutations in the DNA
mismatch repair pathway. BRCA1 and BRCA2, two famous
genes whose mutations confer a hugely increased risk of breast
cancer on carriers.
51. •Cancer therapy procedures such
as chemotherapy and radiotherapy work by overwhelming the
capacity of the cell to repair DNA damage, resulting in cell death.
Cells that are most rapidly dividing — most typically cancer
cells — are preferentially affected
52. Colon cancer is the second leading cause of cancer
death in the United States.
More than 15% of cancer deaths worldwide are
linked to underlying infections or inflammatory
conditions.
53. An irreversible state of dormancy, known as
senescence
Cell suicide, also known as apoptosis or programmed
cell death
Unregulated cell division, which can lead to the
formation of a tumor that is cancerous
54. TA 65
The winners of the 2009 NOBEL PRIZE in MEDICINE were
scientists who discovered that a certain part of our DNA was
responsible for the aging and death of our cells. This DNA segment is
called the telomere. Telomeres are like the little plastic caps on the ends
of your shoelaces. When the plastic cap wears away, the shoelaces fray,
unravel, and don't work anymore. The same goes for telomeres. Over
time, these "DNA caps" breakdown and begin to shorten. When they
shorten far enough, they are unable to protect the rest of the DNA, and
the DNA becomes non-functional. The cell dies, or more precisely it
becomes inactive.
DNA repair and anti aging
55. telomere shortening in humans include: Inflammation, Oxidation, and
Glycation (think sugar). In layman's terms we are talking: bad diet,
stress, lack of exercise, stress, smoking, pollution, stress, plastics, sugar,
stress, heavy metal exposure…
Back to DNA. Telomerase lengthens short telomeres. It rebuilds the
plastic cap on your shoelaces. Telomerase has the potential to make our
DNA stay active and healthy. It has the potential to make people live
longer and stay healthier. Research on animals (and some humans) has
shown unequivocally that re-lengthening short telomeres with telomerase
can reverse heart disease, vascular disease, diabetes, cancer, Parkinson's,
etc.