DNA repair and mutations

DNA and Genetic Information

  • DNA is the carrier of genetic information.

  • Understanding DNA repair and mutations is essential in biology.

Learning Outcomes

  • ALO 1: Explain how DNA damage/errors induce diseases including cancer.

  • ALO 2: Explain how DNA damage/errors induce mutagenesis and chemical polymorphism.

  • ALO 3: Describe the importance of DNA repair mechanisms in controlling/limiting DNA damage.

  • ALO 4: Discuss the role of inheritance in disease genetics.

  • ALO 5: Discuss mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR).

DNA Damage and Cancer

  • DNA damage can lead to diseases, notably cancers.

  • Causes of DNA Damage:

    • Physical: (e.g., radiation)

    • Chemical: (e.g., mutagens)

    • Biological: (viruses, genetic factors)

  • DNA damage is also referred to as errors or lesions that interfere with cell division, increasing cancer risks.

Biological Mutagens

  • Sources:

    • Viral: HPV (cervical cancer), HTLV (lymphoma), Hepatitis B (liver cancer).

    • Bacterial: Helicobacter pylori (stomach cancer).

Chemical Mutagens

  • Mutations resulting from foreign molecules binding to DNA.

  • Examples:

    • Benzopyrene (cigarette smoke)

    • Vinyl chloride (plastics)

    • Aflatoxin (certain moulds)

    • Heterocyclic amines (overcooked foods)

Physical Mutagens

  • Characteristics:

    • Ionizing radiation: Breaks DNA strands (from X-rays, cosmic rays, radon gas).

    • Ultraviolet radiation: Causes DNA to bind improperly (thymine dimers).

    • Natural fibres: Asbestos can cause direct DNA damage.

DNA Damage Details

  • Types of DNA Lesions:

    • Abasic Site: Base missing, intact backbone.

    • this is due to rise of temperature, a drop in PH, or destabilization in the N-glycosidic bonds.

    • Mismatch: Caused by replication errors. spontaneous deamination of cytosine

    • Modified Bases: Alteration of bases, e.g., thymine dimers.

    • Single-stranded Breaks:

    • Nick the sugar-phosphates backbone of one strand.

    • Caused by peroxides, ionizing radiation,radicals.

    • Interstrand Crosslinks: Covalent linkages that block replication.

    • because helicase cant melt apart the strands

    • Double-stranded Breaks: Severe lesions where both backbones are broken often from ionizing radiation.

Viral DNA Damage

  • Oncoviruses: Viral infections can interrupt host genes, leading to increased cell division and cancer risk.

  • Example: HTLV can cause leukemia.

Synergistic Mutagens

  • Mutations in p53 and Ras cooperate to promote cancer, regulating crucial genes for tumor formation.

Chromosomal Damage

  • Translocations: Movement of genes can lead to cancer through upregulation and overexpression.

  • Example: EBV causes Burkitt's lymphoma via translocation involving c-myc.

Burkitt's Lymphoma

  • Characterized by sheets of similar lymphoid cells, high proliferation, and apoptosis.

  • Associated with a reciprocal translocation (t(8;14)) affecting c-myc and gene expression for antibody production.

Genetics of Burkitt's Lymphoma

  • High translocation risk in heavy chain gene locus leading to increased c-myc activity and cancerous lymphocytes.

Mutagenesis Types

  • Inherited mutations: Passed from parents, present in all body cells.

  • Acquired mutations: Develop during a person's life, often in somatic cells, affecting only descendants of the mutated cell.

Chemical Carcinogens

  • All are mutagens. Tested using the Ames test to determine carcinogenic potential.

  • a positive result indicates that this is how it can be carcinogenic

Polymorphism

  • Different alleles in a population, not inherently abnormal.

  • Examples include traits that don’t impact health, such as hair color variations.

DNA Repair Mechanisms

  • Over 100 DNA repair enzymes identified in bacteria; around 130 in humans.

  • Mechanisms:

    • Nucleases to remove damaged DNA.

    • DNA polymerase to replace nucleotides.

    • DNA ligase to seal DNA backbone breaks.

Major Repair Processes

  • Mismatch Repair: Recognizes and corrects replication errors.

    • mut protiens bind and cleave mismatched base pairs

    • cleaveage occurs by exonuclease

    • the gap is filled by DNA Polymerase 1

    • DNA Ligase glues everything

  • Nucleotide Excision Repair: Removes bulky DNA adducts (e.g., UV dimers).

    • Endonuclease cleaves the open strand

    • protiens remove the damaged nucleotides

    • gap is filled

  • Base Excision Repair: Corrects modified bases.

    • DNA glucosylase reconizes the AP site and its base

    • AP endonuclease removes the AP site and neighbouring nucleotides

    • PLOY1 and ligase

Consequences of Repair Failure

  • Xeroderma pigmentosum: Deficiency in nucleotide excision repair linked to skin cancers.

Hereditary Factors in Cancer

  • 5% to 10% of cancers hereditary, especially in unusual types or early ages.

  • Examples of hereditary cancers:

    • Colorectal cancer (APC gene mutation)

    • Papillary renal cancer (MET gene mutations).

Cystic Fibrosis

  • Caused by mutations in CFTR gene, leading to abnormal salt movement and sticky mucus, affecting multiple organs.

Gene Therapy Approaches

  • Targets CFTR correction using induced pluripotent stem cells (iPSCs) and gene editing techniques like CRISPR-Cas9.

Conclusion

  • Understanding DNA damage, mutagenesis, and repair mechanisms is vital for genetics and cancer biology.