Group 5 - THE DNA Damage & Repair MECHANIMpptx

SCIENCE

1. DNA DAMAGE AND REPAIR GROUP #05

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. 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

13. 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.

14. 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

15. 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.

16. 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.

17. 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

18. 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.

19. 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 ).

20. 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.

21. MISMATCH REPAIR: Refers to the rescue system that conserves the DNA sequence by removing the erroneous mismatched, inserted or deleted bases.

22. Steps: Mismatch recognition: Recruitment of related proteins Excision and replacement Gap filling

23. NHEJ REPAIR: Is a pathway that repairs double stranded breaks in the DNA Resection: Loss of nucleotide Causes single stranded overhangs

24. Steps: Resection recognition Recruitment of related proteins

25. Steps: Gap filling

26. REGULATION OF DNA REPAIR:

27. 1.CELLULAR REGULATION DNA Damage Response (DDR) Cellular State and Cell Cycle DNA Repair Enzyme Levels 2. Molecular Regulation: Sensor Proteins: (e.g., ATM, ATR). Transducer Proteins: (e.g., CHK1, CHK2). Effector Proteins: (e.g., DNA polymerases, ligases).

28. 3. Post-Translational Modifications: Phosphorylation Ubiquitination Sumoylation 4. Signaling Pathways in DNA Repair: p53 Pathway BRCA1/BRCA2 Pathway Activation of Cell Cycle Checkpoints Apoptosis Induction

29. 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).

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