Breast cancer

• Breast cancer genes


  Genes that can cause breast cancer when faulty
• BRCA1


  A gene identified as the likely location for breast cancer 1
• Identifying BRCA1


  1. Linkage analysis

  2. Narrowing down the location to a 3.5 million bp region on chromosome 17

  3. Identity finally revealed in 1994
• BRCA2


  A gene found on the end of chromosome 13 that wasn't responsible for every case of inherited breast and ovarian cancers
• BRCA mutation


  Individuals with inherited mutations in either BRCA gene have a very high risk of developing breast and ovarian cancers
• Homologous recombination


  Recombination that occurs between two copies of the same parts of the genome
• Non-homologous recombination


  Recombination that occurs between DNA strands from different parts of the genome
• Homologous recombination in DNA repair

  1. Following Translesion synthesis

  2. During meiosis between arms of the chromosomes
• Homologous recombination


  Provides an avenue for accurate DNA repair when the necessary sequence information is not available from a strand paired with the damaged strand
• NHEJ


  Repair mechanism which doesn't require a long homologous sequence to guide repair
• Whether homologous recombination or NHEJ is used to repair double stranded breaks is largely determined by the phase of cell cycle</b>
• NHEJ can use short homologous DNA sequences called microhomologies to guide repair
• Repair of double stranded breaks by NHEJ pathway can occasionally link segments of DNA from different chromosomes
• Diffusion of DNA within the nucleoplasm is fairly slow so the correct ends of broken chromosomes are generally re-joined together, albeit with a loss of some base pairs
• The deletion of base pairs is generally not detrimental as the majority of the length of most human genes consists of introns that are spliced out
• Translocational chromosomes - two broken ends from different chromosomes - can form chimeric genes
• Homologous recombination


  Recombination that occurs between two copies of the same parts of the genome
• Non-homologous recombination


  Recombination that occurs between DNA strands from different parts of the genome
• Homologous recombination in the cell

  1. DNA repair following Translesion synthesis

  2. During meiosis between arms of the chromosomes (resulting in the mixing of genetic material between the maternal and paternal chromosomes)
• Homologous recombination for DNA repair

  1. Lesion or nick in the backbone of one of the DNA strands

  2. Presence of the SSDNA recruits the RecA protein

  3. RecA protein associates the invading strand with the DNA duplex being invaded

  4. Heteroduplex is formed from the information from both strands

  5. Cutting and joining the ends, the other strand is repaired using systems such as the Excision repair

  6. Could also involve crossover structures known as Holliday Junctions

  
• Double-stranded break repair


  Repair of DS breaks can happen in two ways: Homologous recombination (HR) to obtain instructions from the sister or homologous chromosome for proper repair of breaks, or Joining of ends even if there is no sequence similarity between them (non- homologous end joining)

  
• Double-stranded break repair by Homologous Recombination

  1. Following a DS break nucleolytic degradation of the 5ʹ-terminated strands to generate 3ʹ-ssDNA tails occurs

  2. This process referred to as 5ʹ–3ʹ end resection provides overlaps for strand invasion by homologous recombination to occur

  3. The second processed end of the DNA break engages with the joint molecule by two alternative mechanisms: A second independent invasion via the Double-strand break repair (DSBR) pathway, or Annealing to the displaced strand of the joint molecule via the Synthesis-dependent strand annealing (SDSA)

  
• Non-homologous end joining (NHEJ)

  • DNA repair mechanism which, unlike homologous recombination, does not require a long homologous sequence to guide repair
  • Whether homologous recombination or NHEJ is used to repair double-strand breaks is largely determined by the phase of cell cycle
  • NHEJ can use short homologous DNA sequences called microhomologies to guide repair
  • When the overhangs are perfectly compatible (cohesive ends), NHEJ usually repairs the break accurately
  • Repair of double strand breaks by NHEJ pathway can occasionally link segments of DNA from different chromosomes
  • Diffusion of DNA within the nucleoplasm is fairly slow so the correct ends of broken chromosomes are generally re-joined together – albeit with a loss of some base pairs - before they diffuse too far apart for NHEJ to be efficient
  • The deletion if base pairs is generally not detrimental as the majority of the length of most human genes consists of introns that are spliced out
  • Translocational chromosomes – two broken ends from different chromosomes - Chimeric genes