The document summarizes key aspects of the cell cycle, DNA damage and repair mechanisms. It describes the phases of the cell cycle including interphase and mitosis. It discusses regulation of the cell cycle by cyclin-dependent kinases and checkpoints. It also covers how radiation affects different cell cycle phases and types of DNA damage induced. Finally, it provides an overview of various DNA damage repair pathways such as base excision repair, nucleotide excision repair, double-strand break repair and mismatch repair.
It describes relationship between radiation dose and the fraction of cells that “survive” that dose.
This is mainly used to assess biological effectiveness of radiation.
To understand it better, we need to know about a few basic things e.g.
Cell Death
Estimation of Survival / Plating Efficiency
Nature of Cell killing etc.
A cell survival curve is the relationship between the fraction of cells retaining their reproductive integrity and absorbed dose.
Conventionally, surviving fraction on a logarithmic scale is plotted on the Y-axis, the dose is on the X-axis . The shape of the survival curve is important.
The cell-survival curve for densely ionizing radiations (α-particles and low-energy neutrons) is a straight line on a log-linear plot, that is survival is an exponential function of dose.
The cell-survival curve for sparsely ionizing radiations (X-rays, gamma-rays has an initial slope, followed by a shoulder after which it tends to straighten again at higher doses.
It describes relationship between radiation dose and the fraction of cells that “survive” that dose.
This is mainly used to assess biological effectiveness of radiation.
To understand it better, we need to know about a few basic things e.g.
Cell Death
Estimation of Survival / Plating Efficiency
Nature of Cell killing etc.
A cell survival curve is the relationship between the fraction of cells retaining their reproductive integrity and absorbed dose.
Conventionally, surviving fraction on a logarithmic scale is plotted on the Y-axis, the dose is on the X-axis . The shape of the survival curve is important.
The cell-survival curve for densely ionizing radiations (α-particles and low-energy neutrons) is a straight line on a log-linear plot, that is survival is an exponential function of dose.
The cell-survival curve for sparsely ionizing radiations (X-rays, gamma-rays has an initial slope, followed by a shoulder after which it tends to straighten again at higher doses.
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
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.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...GL Anaacs
Contact us if you are interested:
Email / Skype : kefaya1771@gmail.com
Threema: PXHY5PDH
New BATCH Ku !!! MUCH IN DEMAND FAST SALE EVERY BATCH HAPPY GOOD EFFECT BIG BATCH !
Contact me on Threema or skype to start big business!!
Hot-sale products:
NEW HOT EUTYLONE WHITE CRYSTAL!!
5cl-adba precursor (semi finished )
5cl-adba raw materials
ADBB precursor (semi finished )
ADBB raw materials
APVP powder
5fadb/4f-adb
Jwh018 / Jwh210
Eutylone crystal
Protonitazene (hydrochloride) CAS: 119276-01-6
Flubrotizolam CAS: 57801-95-3
Metonitazene CAS: 14680-51-4
Payment terms: Western Union,MoneyGram,Bitcoin or USDT.
Deliver Time: Usually 7-15days
Shipping method: FedEx, TNT, DHL,UPS etc.Our deliveries are 100% safe, fast, reliable and discreet.
Samples will be sent for your evaluation!If you are interested in, please contact me, let's talk details.
We specializes in exporting high quality Research chemical, medical intermediate, Pharmaceutical chemicals and so on. Products are exported to USA, Canada, France, Korea, Japan,Russia, Southeast Asia and other countries.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Factory Supply Best Quality Pmk Oil CAS 28578–16–7 PMK Powder in Stockrebeccabio
Factory Supply Best Quality Pmk Oil CAS 28578–16–7 PMK Powder in Stock
Telegram: bmksupplier
signal: +85264872720
threema: TUD4A6YC
You can contact me on Telegram or Threema
Communicate promptly and reply
Free of customs clearance, Double Clearance 100% pass delivery to USA, Canada, Spain, Germany, Netherland, Poland, Italy, Sweden, UK, Czech Republic, Australia, Mexico, Russia, Ukraine, Kazakhstan.Door to door service
Hot Selling Organic intermediates
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
1. CELL CYCLE,
APPLICATIONS,
DNA DAMAGE AND
REPAIR
By Dr. Shounak J. Kamat
1st year Resident
DNB Radiation Oncology
HCG Cancer Centre- Borivali-
Mumbai
Guide:- Dr. Trinanjan Basu
2. Overview
Cell Cycle
Regulation of Cell Cycle
Effect of Radiation on Cell Cycle
DNA Damage
DNA Repair Mechanisms
3. Cell Cycle
A cell cycle is a precisely programmed series of
events which enables a cell to duplicate its
contents and divide into 2 daughter cells
It has the following phases:-
1] G1 phase
2] S phase Interphase
3] G2 phase
4] M phase or the Mitosis phase
5] G0 or the resting state of cells that
have withdrawn from active cell cycle
4. Interphase
It is the phase in which cells spend most of their lives preparing for mitosis.
It is divided into 3 stages:-
1] G1 phase – phase of cell growth and protein synthesis
2] S phase – phase where DNA and centrosomes are replicated
3] G2 phase – phase where energy replenishment, mitotic specific protein
synthesis, cytoskeleton dismantling and additional growth take
place.
7. Prophase
In this phase the chromosomes which
were invisible microscopically during
interphase begin to condense and
become visible
Also centrosomes begin to assemble at
the poles of cells
8. Metaphase
In this phase the chromosomes align
along a plane that bisects the cell and
become attached to microtubule fibres
of mitotic spindle
Also the nuclear membrane
disappears at this time
9. Anaphase
During this phase the chromatids are
pulled apart by the mitotic spindle to the
opposite poles of the cell.
10. Telophase and Cytokinesis
The chromatids cluster into two sets ,
they de-condense and a new nuclear
membrane forms around each set of
chromatids
During this time the cytoplasm of the cell
also divides into two thus yielding two
daughter cells
12. Cyclin Dependent Kinases
They are serine/threonine kinases that sequentially regulate progression of cell
through the cycle via phosphorylation.
They do this via 4 mechanisms
Association with cyclins
Assosiation with CDK inhibitors
Addition of phosphate groups to activate CDK activity
Deletion of phosphate groups to inhibit CDK activity
14. Association with Inhibitors
2 Families of inhibitors are involved in regulating cyclin–cdk activity:
- p16 INK 4a family
- p21 Cip/Kip family
INK Protein binds to cdk 4/6 and interferes with its binding to cyclin D
Cip/Kip family of inhibitors interact with both cyclins and their associated cdks
(mainly with cdk2 and cyclin E) and disable kinase activity
ubiquitin-mediated degradation of inhibitors ensures that the inhibitors are
present during a specific period of time during the cell cycle.
15. Regulation by Phosphorylation
This involves both activation and inhibition
Two steps are required for cdks to become active:
1] Dephosphorylation of the inhibitory phosphate groups by cdc25 phosphatases
2] Phosphorylation of a central threonine residue- Thr161 by cdk-activating kinase
(CAK).
16. Cell Cycle Checkpoints
Signaling pathways that sense and
induce a cellular response to DNA
damage.
The components are DNA damage
sensors, signal transducers, or
effectors.
Disruption of checkpoint function
leads to genomic and chromosomal
instability leading to mutations that
can induce carcinogenesis
17.
18.
19. Role of p53 Gene
p53 is a tumor suppressor gene that is critical in the pathway that arrests the G1
checkpoint.
In response to DNA damage, ataxia telengectasia mutated (ATM)
autophosphorylates and releases active monomer which phosphorylates p53 and
activates it.
Activated p53 enhances p21 gene expression which results in sustained inhibition
of G1 cyclin and Cdks.
This in turn inhibits Rb phosphorylation and progression from G1 to S.
Mutation in this gene compromises this checkpoint function and results in
damaged dna replication leading to carcinogenesis.
21. In Chinese hamster cells
Most sensitive cells to Radiation are the ones
in M and G2 [ steep curve, no shoulder]
Most radioresistent cells are in late S phase
[less steep curve but very broad shoulder]
Other phases G1 and Early S are intermediate
between the two extremes.
22. In HeLa Cells
Similar to the hamster cells in most
aspects
Major difference is length of G1 phase in
HeLa cells is appreciably long and at the
beginning of G1 there is a peak of
radioresistance followed by a trough of
radiosensitivity towards end of G1.
23.
24. CELL CYCLE SPECIFIC DRUGS
During M Phase:-
Taxanes and Vinca Alkaloids cause a synergistic action by acting on DNA and causing its damage.
During S Phase:-
Drugs such as Capecitabine, Gemcitabine and 5-fluorouracil inhibit nucleotid formation and DNA replication.
Since this phase is radioresistant, they cause a synergistic action with radiation.
During G2-M phase:-
Drugs such as Topoisomerase Inhibitors arrest the cells in G2M phase which is a radiosensitive phase thus
causing increase in the effect caused by radiation.
25. EFFECT OF OXYGEN ON CELL CYCLE
OXYGEN ENHANCEMENT RATIO (OER)
Ratio of doses administered under hypoxic to aerated conditions needed to
achieve same biologic effect.
OER for Xrays and Gamma rays has a value between 2.5 to 3.5.
With respect to cell cycle the OER in the G2 and M phase and also in the G1
phase is lower than in S phase because of the radiosensitivity of these phases.
Thus maintaining an aerated state helps in increasing the efficacy of the
radiation treatment.
27. Structure of DNA
DNA is made up of 2 strands and
arranged in a helical pattern.
The strands are formed of a Deoxy
ribose sugars and phosphate
molecules.
On those strands are the purine and
pyrimidine molecules which are
bound by Hydrogen bonds.
28. Effect of Radiation on DNA
Direct Effect Indirect Effect
There are 2 effects :-
30. Types of DNA damage
Single strand breaks
Double strand breaks
DNA crosslink formations
Radiation induced chromosome and chromatid aberrations.
31. Single strand breaks
This occurs when one strand of DNA is
damaged or broken.
More common type of defect
Is readily repaired because of availability
of template on intact opposite strand.
Of lesser biologic significance
Approx. 1000 SSBs per cell after 1 -2 Gy
32. Double strand break
This occurs when both the strands of
DNA are damaged.
Less common defect
Has more significance since this takes
time to be repaired and can result in
mutations, carcinogenesis and cell
death
Approx. 40 DSBs after 1-2 Gy
33. Measuring DNA Strand Breaks
Pulsed Field Gel Electrophoresis (PFGE)
Single-cell Gel Electrophoresis (also known as the comet assay).
DNA damage induced nuclear foci assay
34. DNA crosslink formations
This occurs in oxidative stress when O2 free radicals form intermediaries which then
react with DNA nucleotides and form covalent links between the nucleotides.
They can be of the following types
Intrastrand crosslinks- when crosslinking occurs within same strand
Interstand crosslinks- when crosslinking occurs between opposite strands of DNA
DNA Protein crosslink- between DNA and an oxidised protein
35.
36. Radiation Induced Chromosome Aberrations
Occurs when cells are irradiated in the early interphase stage before the chromosome
has been duplicated.
Can be of the following types
1] Dicentric chromosome 2] Ring aberration
37. Radiation Induced Chromatid Aberration
Occurs when the cell is irradiated in the late interphase after the chromosome has
duplicated
Anaphase Bridge
40. Base Excision Repair
Removal of the defective base by a
Glycosylase/DNA lyase
Followed by removal of the sugar
residue by an apurinic endonuclease
1 (APE1)
then replacement with the correct
nucleotide by DNApolymerase
completed by DNA ligase
the complex of replication factor C
(RFC)/proliferating cell nuclear
antigen (PCNA)/DNApolymerase /
performs the repair synthesis,
the overhanging flap structure is
removed by the flap endonuclease 1
(FEN1)
DNA strands are sealed by ligase I
Single Base Defect Multiple Base Defect
41.
42. Nucleotide Excision Repair
Nucleotide excision repair (NER) removes bulky adducts in the DNA such as pyrimidine
dimers.
Subdivided in 2 pathways:-
1] Global genome repair:- to repair DNA that encodes or does not encode for genes.
2] Transcription coupled repair:- to repair DNA strands of actively transcribed genes
Post DNA damage, RNA polymerase blocks access to the site of damage. The TC-NER
prevents this blockade by removing RNA polymerase from the site.
43. The 2 mechanisms differ only in detection
of lesion, remaining pathway is same.
The essential steps in this pathway are:-
(1) damage recognition
(2) DNA incisions that bracket the lesion
usually 24 to 32 nucleotides in length.
(3) removal of the region containing the
adducts
(4) repair synthesis to fill in the gap
region
(5) DNA ligation
44. DNA Double-Strand Break Repair
Homologous Recombination
Repair [HRR]
This requires an undamaged DNA
strand as a participant in repair as a
template
Error free process since repair is
performed by copying information from
undamaged homologoes chromatid.
Primararily occurs in late S/G2 phase
when undamaged sister chromatid is
available to act as template
Non Homologous End Joining
[NHEJ]
This mediates end to end joining
Error prone and accounts for many
premutagenic lesions induced in DNA by
ionizing radiation
Occurs in G1 phase when template
doesn’t exist..
45. NHEJ
NHEJ can be divided into five steps:
(1) end recognition by Ku binding
(2) recruitment of DNA-dependent protein
kinase catalytic subunit (DNA-PKcs)
(3) end processing
(4) fill-in synthesis or end bridging
(5) ligation
46. HRR
In this, two of the protiens
used are encoded by genes
BRCA 1 and 2
Accessory factors such as
Rad54, Rad 54B and Rdh54
help recognize and invade
the homologous region.
After D-loop formation,
DNA polymerase is involved
to elongate the invading
strand.
47. Cross Linking Repair
Steps
Signals for repair is stalling of the DNA replication fork.
The crosslink is removed in a multistep process:-
1] Crosslink is removed from one strand by a NER, resulting in a
strand break and a DNA adduct.
2] The strand break requires HRR for restitution.
3] Finally, the adduct that remains is removed by NER
48. Miss Match Repair
The mismatch repair (MMR) pathway removes
base–base and small insertion mismatches that
occur during replication.
Steps
1] The mismatch must be identified by
sensors that transduce a signal of a
mismatched base repair
2] MMR factors are recruited
3] The newly synthesized strand harboring
the mismatch is identified and the
incorrect/ altered nucleotides are excised
4] Resynthesis and Ligation of the DNA.