PolyADP-ribose polymerase (PARP) plays a key role in the repair of DNA single st
ID: 220735 • Letter: P
Question
PolyADP-ribose polymerase (PARP) plays a key role in the repair of DNA single strand breaks. In the presence of the PARP inhibitor olaparib, single-strand breaks accumulate. When a replication fork encoutners a single-strand break, it converts it to a double-strand break, which in normal cells is then repaired by homologous recombination. In cells defective for homologous recombination, however, inhibition of PARP triggers cell death.
Patients who have only one functional copy of the Brca1 gene, which is required for homologous recombination, are at much higher risk for cancer of the breast and ovary. Cancers that arise in these tisues in these patients can be treated with olaparib.
Explain how it is that treatment with olaparib kills the cancer cells in these patients but does not harm their normal cells.
Explanation / Answer
Answer:
Base excision repair mechanism is involved in the repair of single stranded breaks in DNA. PolyADP-ribose polymerase plays a critical role in the repair of single strand breaks in DNA. When PARP enzyme is inhibited, then the single strand breaks keep on accumulating and converts into double strand breaks.Along with PARP, other mechanisms like homologous recombination and the non homologous end joining are also involved in repair of double strand breaks in DNA.
Since BRCA1 is involved in the repair of double strand breaks by homologous recombination, therefore patients who have one functional copy of the Brca1 gene have defective homologous recombination system and are susceptible to the impairment of the Base excision repair mechanism. As a result, such patients are even more dependable on PARP mediated repair and therefore extremely sensitive to PARP inhibitors. PARP and BRCA are also synthetic lethal which means that if both genes are lost simultaneously, it will lead to cell death.
PARP inhibitors are specific to cells that have mutation in Brca1 gene or have dysfunctional Brca1 gene. Normal cells, on the other hand, are not affected much since homologous recombination mechanism is still intact in such cells and also normal cells don''t replicate the DNA as frequently as cancer cells.