KINESIOL 1Y03 Lecture Notes - Lecture 60: Poly (Adp-Ribose) Polymerase, Tumor Suppressor Gene, Sister Chromatids
20 Jun 2018
School
Department
Course
Professor
Surgery and Anaesthesia Sheena Cheung ssc211
Module 1: Cancer repair and regeneration With additions from ABS’ notes
61
a. Base specific DNA glycosylase detects altered base and removes it to produce an abasic
site
b. AP endonuclease and phosphodiesterase remove sugar phosphate
c. DNA polymerase fills to repair the damage: requires poly ADP ribose polymerase PARP
d. DNA ligase seals the repair
[DSB] Double strand break repair
o [HR] Homologous recombination: double strand break repair mechanism
Complex of proteins form at the site of the double strand break. Homologous
sister chromatid is brought in as a template to repair the broken strand using
recombination proteins. The original chromatid will be separated one into the
repair strand one in the original and the other side is base paired to give two new
complete double strands.
Proteins includes tumour suppressor gene products BRCA1/2
Quite slow, energy consuming and requires sister chromatid
Homologous recombination repair occurs late in Sphase when sister chromatids
have been synthesised
o [NHE] Non-homologous end joining
Complex forms by DNA-PK between the two strands
Other proteins assemble at the DNA-PK complex to religase the DNA strands
Synthetic lethality: cancer treatment exploiting dsDNA repair
Increasing the therapeutic index of a drug by exploiting tumour specific genetic mutations
o Because the mutant cancer cell is missing the gene for specific recombinant proteins, a
PARP-inhibitor drug can serve as the 'second hit' to inhibit its remaining mechanism for
repairing dsDNA damage.
BRCA2 secondary (reversion) mutation: secondary mutation undoes the mutation it started
with to regain homologous recombination competence to stay alive
Apoptotic resistance
Increase in survival signal to prevent apoptosis
Oncogene/tumour suppress gene mutation to inactivate pro-apoptotic signals
Document Summary
[hr] homologous recombination: double strand break repair mechanism (cid:120) complex of proteins form at the site of the double strand break. Homologous sister chromatid is brought in as a template to repair the broken strand using recombination proteins. [nhe] non-homologous end joining (cid:120) complex forms by dna-pk between the two strands (cid:120) other proteins assemble at the dna-pk complex to religase the dna strands. Synthetic lethality: cancer treatment exploiting dsdna repair (cid:120) Increasing the therapeutic index of a drug by exploiting tumour specific genetic mutations: because the mutant cancer cell is missing the gene for specific recombinant proteins, a. Parp-inhibitor drug can serve as the "second hit" to inhibit its remaining mechanism for repairing dsdna damage. (cid:120) brca2 secondary (reversion) mutation: secondary mutation undoes the mutation it started with to regain homologous recombination competence to stay alive. Increase in survival signal to prevent apoptosis (cid:120) (cid:120) oncogene/tumour suppress gene mutation to inactivate pro-apoptotic signals.
