2. GROUP MEMBERS:
Aima Saleem
Alina Nasir
Eman Nadeem
Mahishba Ikram
Minaal Tariq
Noor E Sahar
3. DNA DAMAGE:
DNA damage refers to any change or
alteration in the chemical structure of DNA.
4. SOURCES OF DNA DAMAGE:
Exogenous:
- Ionizing radiation (e.g.,
X-rays, gamma rays)
- Ultraviolet (UV)
radiation from the sun
- Chemicals (e.g.,
tobacco smoke, certain
drugs)
Endogenous:
- Reactive oxygen
species (ROS) produced
during normal cellular
metabolism
- Errors during DNA
replication
5. CONSEQUENCES OF DNA DAMAGE:
Mutations: Changes in the DNA sequence, leading to altered gene
function.
Cell Death: Damaged cells undergo apoptosis (programmed cell death).
Cancer: Accumulation of mutations can transform normal cells into
cancerous ones.
Aging: DNA damage accumulation over time contributes to the aging
process.
6. DNA REPAIR:
DNA repair is the molecular process by which a cell identifies and corrects damage
to the DNA molecules that make up its genome, ensuring the preservation of
genetic information and the maintenance of genomic integrity.
7. DNA DAMAGE AND REPAIR:
Detection of damage
Activation of repair pathways
Repair Mechanisms
Maintenance of genomic integrity
Cellular responses
Regulation and coordination
8. IMPORTANCE:
Essential for maintaining genomic integrity.
Prevents mutations that can lead to diseases, including cancer.
Vital for cellular function, survival, and overall organism health.
9. TYPES OF DNA DAMAGE:
DNA crosslinking
DNA strandbreaks
Alkylation of bases
Loss of bases
10. DNA CROSSLINKING:-
DNA crosslinking arises from agents reacting with DNA
nucleotides, creating covalent bonds between two adjacent
bases.
Main factors are EXOGENEOUS.
This crosslink can occur within the same strand
(intrastrand) or between opposite strands of double-
stranded DNA (interstrand)
11. CONSEQUENCES:
UV light can cause molecular crosslinks to form between two pyrimidine
residues.
In a pyrimidine dimer, two adjacent pyrimidine bases form covalent limkage.
The dimer causes a twist in the helix, thus interfering with the normal
interaction between thymine and adenine.
50-100 such reactions continuously occur in skin during exposure to sunlight
uncorrected lesions trigger cell death.
12.
13. DNA STRAND BREAKS:-
Ionizing radiation from radioactive decay or cosmic rays can cause DNA strand
breaks.
Crosslinks can also lead to DNA strand breaks if damaged DNA undergoes
replication.
Crosslinked DNA can cause topoisomerase enzymes to stall in the transition state
inhibiting its normal functioning.
Instead of relieving supercoiling and resealing the backbone, the stalled
topoisomerase remains covalently linked to the DNA
14. CONTINUED:
This results in single stranded or double
stranded strand breaks in DNA.
These DNA strand breaks can serve as a
damage sensor within the cell, initiating DNA
repair processes.
15. Alkylation of bases:
Alkylation of DNA bases refers to the process of adding alkyl
groups (methyl, ethyl, etc.) to the nitrogenous bases of DNA
molecules.
Alkylating agents: Can result from exposure to
chemicals, environmental factors, or cellular metabolism
byproducts.
Affected Bases: purine bases (adenine, guanine) Methyl group
16. Consequences:
Abnormal DNA structures, impacting
stability.
Interferes with DNA replication and
transcription, leading to mutations
Unrepaired damage can contribute to
mutations, potentially leading to cancer.
17. Example:
Ethylmethane sulfonate (EMS), which transfers ethyl (CH3-CH2) groups to DNA.
The product of this methylation, O6-rthylgaunine, often mispaires with thymine,
resulting in the change of G:C base pair into an A:T base pair when the damaged
DNA is replicated.
18. Base loss:
Base loss in DNA refers to the removal of one or more
nitrogenous bases from the DNA molecule
Causes:
Chemical Exposure, Endogenous Factors
Mechanisms:
Deamination, Chemical Damage
19. Consequences:
Formation of Apurinic or Apyrimidinic (AP) Sites , Mutation Risk
Example:
Cytosine deamination, a common DNA damage, can result in base
loss, converting cytosine to uracil. The subsequent
apurinic/apyrimidinic (AP) site formation during repair may lead to
mutations during DNA replication, impacting genomic stability.
20. DNA Repair Pathways:
Direct Damage Reversal:
Simplest repair mechanism
Single polypeptide chain with enzymatic properties
Binds to damage and restores DNA in a single-
reaction step
Example enzyme: O6-methylguanine-DNA methyl
transferase (MGMT).
21.
22. BASE EXCISION REPAIR (BER):
Targets small, non-helix-distorting lesions.
Involves enzymatic steps:
• DNA glycosylase recognizes and removes damaged base’
• Creates an apurinic/apyrimidinic (AP) site
• AP endonucleases incise DNA backbone at the AP site, causing a strand
break
• DNA polymerase fills in the missing nucleotide.
• DNA ligase seals the nick, completing the repair.
23.
24. MISMATCH REPAIR:
Refers to the rescue system that conserves the DNA
sequence by removing the erroneous mismatched,
inserted or deleted bases.
34. Challenges:
1.Complexity of Pathways
2.Resistance to Therapy
Clinical Implications:
Cancer: Many cancers involve mutations in DNA repair genes (e.g.,
BRCA1/2 in breast cancer).
Aging: Accumulation of DNA damage over time is a contributing
factor to aging and age-related diseases.
Therapeutic Targets: Drugs targeting specific DNA repair
pathways (e.g., PARP inhibitors in cancers with BRCA mutations).