DNA replication dynamics
Every time a cell divides it must replicate all its genetic information and divide it equally into the two daughter cells. The cell’s DNA must be timely and accurately replicated before cell divides, in order to prevent loss or duplication of essential genetic information. Additionally, mistakes in DNA replication can cause accumulation of mutations. Mutations in DNA can kill cells, stop them from dividing or may lead to uncontrolled cell proliferation, a hallmark of cancer.
We have discovered Fork Speed Regulatory Network (FSRN), an integrated molecular mechanism that regulates the velocity of DNA replication at the level of individual replication forks. FSRN consists of PARP and the p53/p21 pathways and prevents unrestrained progression of replication forks. Moreover, we showed that PARP inhibitor, a chemotherapy drug commonly used against breast and ovarian cancer, does not stall or collapse forks, as previously proposed, but rather increase replication rate. Our goal is to understand the underlying mechanisms of action of PARP inhibitors on replication rate. By finding out the exact mechanism by which PARP inhibition increases speed of DNA replication, we aim to shed light on molecular mechanisms of DNA replication of normal cells and expose potential vulnerability of cancer cells.
- DNA replication
- DNA polymerases
- Okazaki fragment processing
- Fork reversal
- Replication gap suppression
- DNA polymerases responsible for PARP inhibitor-induced replication fork acceleration
- Okazaki fragment processing and lagging strand synthesis in regulation of replication fork dynamics
- Suppression of fork reversal as potential mechanism of PARP inhibitor-induced replication fork acceleration