Scientists uncover novel DNA repair mechanism for key cancer target

Scientists at the Francis Crick Institute, in collaboration with Artios, have identified how an enzyme involved in DNA repair (POLQ), becomes vital to the survival of certain cancers, if the cancer cells lose the ability to use a more common method of DNA repair.

The work uncovers an unappreciated role for POLQ in responding to DNA replication stress, providing the scientific underpinnings for a Phase I clinical trial evaluating the effects of blocking this enzyme in cancer patients.

Polymerase theta (POLQ) is a DNA repair enzyme that is selectively upregulated and highly active in many types of cancers. Research has suggested 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,” explained 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 tumour survival.”

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.

In their research, published online in Molecular Cell today (30 November), the scientists studied how DNA gaps are repaired in human cancer cells using advanced imaging tools that monitor DNA replication in real time. They found that POLQ provides a vital repair mechanism in cancer cells unable to repair DNA gaps using a common method called homologous recombination.

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