13. DSB Repair Deficiency

• SCID = severe combined immunodeficiency disorder

  • occurs due to DNA DSBs being physiologically induced during V(D)J recombination - normally NHEJ is used here but SCID have mutations in NHEJ
  • leads to DNA damage response being activated and cells being apoptosed
  • no B cells produced that produce Ig as these cells apoptose
• normally in V(D)J recombination

  • RAG1/2 cuts randomly within the gene
  • NHEJ joins two ends together
  • combines V and D segments
  • then repeats to combine VD and J
  • creates variable region of Ig
  • DNA that is cut out must be circularised to not be identified as DSB
• in mice, if NHEJ and RAG1/2 genes are knocked out, the B cells survive as no DSBs are produced

  • dont produce Ig

  if we add pre-recombined BCR the cells produce Ig
• patients with XRCC4 mutations develop microencephaly and growth retardation but not SCID - unsure why dont develop SCID

  • NHEJ severely affected but not absent
• why do mutations in NHEJ cause microencephaly?

  • in development neuro-progenitor cells rapidly expand to produce sufficient number of cells for brain to develop
  • DSBs generate naturally in S phase due to replication fork collapse - neural progenitor cells have increased proliferation so increased DSBs
  • possible that NHEJ is required to repair some of these
  • reduces total pool of cells, causing small brains and heads
• mutations in HR genes do not usually cause immunodeficiency

  • those that do have issues with class switch recombination, leading to decreased Ig production
• mutations in mre11 and rad50 do not cause immunodeficiency for an unknown reason
• neuroprogenitor cells have a high dependence on homologous recombination for repair, so if there is a mutation affecting HR this causes microencephaly
• cerebellar ataxia is where the cerebellum starts to degenerate once the brain is fully developed, has an unknown cause

  • found in homologous repair mutations