DNA Repair Enzyme Shows Promise as Cancer Drug Target

Francis Crick Institute researchers have identified how an enzyme involved in DNA repair becomes vital to the survival of certain cancers that have lost the ability to repair DNA by another, more common pathway. The findings suggest the enzyme, Polymerase theta (POLQ), could be a novel cancer target.

When DNA is replicated, the two strands that make up the double helix are separated, and each strand is used as a template to synthesize a new double helix. However, this process can go wrong, and lead to errors such as the formation of gaps in DNA. There are several types of DNA repair mechanisms that are designed to repair these errors so that replication can continue normally.

Cancer cells, including cancers associated with the BRCA gene, often lose the ability to use the common DNA repair mechanism homologous recombination. Using advanced imaging tools that monitor DNA replication in real time, the Crick team showed that POLQ steps up to the task.

This discovery agrees with prior work showing POLQ is selectively upregulated and highly active in many types of cancers, and provides evidence that blocking POLQ can prevent some cancer cells from repairing their DNA, ultimately leading to cancer cell death.

“There are several properties of POLQ that make it an exciting target to explore as a potential Achilles Heel for treating different cancers,” says Simon Boulton, senior author, principal group leader at the Crick and scientific co-founder and VP of scientific strategy at Artios. “POLQ is mainly expressed in cancer cells but is virtually absent in healthy cells. Many cancers become reliant on POLQ to repair DNA damage, a key response important for tumor survival.”

POLQ fills in the DNA repair gap to allow replication to continue and the cancer cells to survive, but this comes at a cost. POLQ’s gap-filling activity is highly error prone and leads to an increased rate of mutations. When the researchers inhibited POLQ in cells deficient for homologous recombination (e.g., BRCA gene mutations) or in combination with inhibitors of the DNA repair enzyme called PARP, DNA gaps accumulated, leading to cancer cell death.

“While it is known that blocking POLQ and homologous recombination at the same time hinders DNA repair, our research now provides the scientific foundation to explain how,” says Ondrej Belan, first author and postdoctoral researcher at the Crick. “This mechanistic understanding of how POLQ inhibitors work will help us explore their full potential, including what other treatments they can be combined with and what cancers they are most effective against.”

The findings were published recently in Molecular Cell.