3

• Mutation is an abnormal gene change.

  There are 2 types – acquired and inherited

  Inherited – present in every cell in body. Passed down from parent to child

  Acquired – get mutations at some point of your life. More common than inherited. Present only in one cell and is passed down to offspring of that cell.

  Mutations can produce polymorphism
• Mutagenesis – mutagens are all chemical carcinogens.

  Ames test – helps to see if a substance can be carcinogenic.

  Bacterial cultures are present to see any mutations. Liver extract with chemical is added to these cultures. Added after metabolic activation has occurred.

  Positive result – substance can be carcinogenic
• DNA damage – repaired by DNA repair enzymes.

  Rate error of mitotic cell increases carcinogens. Interfere with normal repairing.
•  DNA lesions – damaged sites on DNA structure

  Abasic site – DNA base missing. Due to pH drop, temperature rise and base alkylations.

  Mismatch – replication errors. Due to tautomerization and spontaneous deamination.

  Modified bases – lesions due to base changes. UV induced.
• Mismatch lesion

  A) mismatch

  
• Abasic lesion

  A) abasic site

  
• modified bases

  A) modified bases

  
• Single strand breaks – gap in one strand of backbone. Due to oxygen radicals, ionizing radiation and peroxides.

  Interstrand crosslinks – covalent linkage between 2 strands. No DNA replication past lesion. Helicase cant break linkage.

  Double stranded breaks – lethal. Gaps in both strands of backbone. Due to ionizing radiation
• Single stranded breakage

  A) single stranded break

  
• interstrand crosslinks

  A) interstrand crosslinks

  
• double stranded breals

  A) double stranded breaks

  
• Viral DNA damage – oncovirus can infect and cause tumor.

  Viral replication - interrupt host replication. Cell cycle is affected.

  Oncoviruses may use host for increased replication.
• Reverse trancribed DNA inserted into host cell. Host cell begins to replicate oncogenes as well as viral proteins.
• Chromosome damage – cell cycle genes moved to another chromosome due to chromosomal translocation.
• DNA repair mechanism – nuclease cuts out damaged DNA

  DNA polymerase adds correct nucleotide

  DNA ligase closes gaps on backbone
• 3 major DNA repair mechanisms - mismatch, base excision and nucleotide excision repair.
• Mismatch repair – after DNA replication new strand not methylated.

  Mismatched base pair cleaved by mut proteins

  Cleavage by exonuclease

  Gap filled by polymerase I

  Ligase closes gaps on backbone
• Nucleotide excision repair – cleavage by endonuclease. Damaged nucleotides removed by proteins. Gap filled by polymerase I. gap on backbone closed by ligase.
• Base excision repair – DNA glycosylase forms abasic site (AP). AP endonuclease removes AP site. DNA polymerase I fills gaps. DNA ligase closes gaps on backbone.
• Other DNA repair mechanisms – no parental strand – homologous chromosome can replace damaged chromosome

  No parental strand or homologous chromosome – non homologous chromosome can replace damaged chormosome
• Without DNA damage – xeroderma pigmentosum – nucleotide excision repair enzyme defect. Leads to skin cancer. DNA damage can’t be repaired due to UV light.
• Gene mutations lead to cancer. 2 genes involved in cancer.

  Oncogenes – genes that turn normal cells to cancer cell.

  Tumour suppressor genes – normal genes that control cell division repair DNA damage.

  Tumour suppressor inactivation - cancer

  Oncogene activation - cancer
• Protoncogenes – C-myc and Ras

  Tumor suppressor genes – BRAC 1 and 2, P53 and P16
• synergistic mutagens – in the same cell if p53 and Ras are mutated, they can control a group of genes that can lead cells to become cancerous and make tumors grow.
• Inheritance and cancer genetics – there is an increased risk of cancer when a faulty gene is passed down from parents to child.

  Cases of rare cancer, cancers at young ages, multiple cancers in one person…

  Hereditary cancers are colorectal and papillary renal cancer