09. DNA Damage Recognition

• one unrepaired double stranded break is enough damage to kill a cell
• double stranded breaks are detected by two complexes:

  • ku70/ku80 heterodimer - repairs via NHEJ
  • mre11/rad50/nsb1 complex - repairs via HR
• ku heterodimer sensing dsbs:

  1. binds to DNA ends
  2. binds PAX, which binds to itself and Ku and KBD (Ku binding domains)
  3. DNA PK slides on and binds through DIM
  4. DNA PK activates and phosphorylates itself and histone H2AX
• mrn complex sensing dsbs:

  1. binds DNA through mre11
  2. ATM binds to AIM motif on NSB1
  3. ATM phosphorylates itself and H2AX
  4. MDC1 binds phosphorylates H2AX
  5. recruits PARP1 which creates chains of ADP ribose
• the cell cycle affects whether Ku or MRN complex binds

  • Cdk phosphorylates CtiP which can then binds to NBS1 and help activate its ability to resect ends