Research from the Toledo lab reveals a key property of DNA replication that could be exploited for treating human disease
In a new study published in the journal Cell Reports, the Toledo lab has shown that DNA replication is carried out in a much more loose way than previously thought. Because DNA synthesis is performed differently at the leading strand (continuously and forward) and at the lagging strand (discontinuously, backwards), scientists had assumed that this two activities must be tightly coordinated at the replication fork.
However, this new study shows that when lagging strand synthesis is slowed down (by using an inhibitor of the DNA primase POLA1), the leading strand continues unperturbed. The unwinding of the incoming double stranded DNA molecule causes a very rapid accumulation of single stranded DNA at the lagging strand, eventually triggering a massive DNA fragmentation called replication catastrophe. These results show that lagging and leading strand synthesis act independently, a property that could be used to artificially induce replication catastrophe in cancer cells by inhibiting POLA1.
The Toledo lab now wants to identify novel compounds that interfere with POLA1 and might be useful as cancer treatments in the future.