DNA repair pathway linked to hereditary breast, ovarian and prostate cancer clarified

A DNA repair pathway has been revealed to be dependent on an enzyme linked with hereditary breast cancer, ovarian cancer, and prostate cancer.

Theta-mediated end joining (TMEJ) is a mechanism used within cells to repair double-stranded DNA breaks. New research shows that this process relies on an enzyme called DNA polymerase theta (Polθ), which previous research has shown is pivotal to cell survival in cancers driven by BRCA1 or BRCA2 mutations.

'People with these breast cancer mutations, their cancers rely on polymerase theta's repair pathway to keep the tumours alive and repair DNA damage in the cancerous tissue,' said Dr Susanna Stroik from the University of North Carolina at Chapel Hill who is first author of the study.

Dr Stroik and her colleagues have published research in Nature, the results of which set out the full TMEJ pathway step by step, and details how Polθ works closely with another enzyme, polymerase delta (Polδ) throughout TMEJ.

When a double stranded break happens, single-stranded DNA tail ends are exposed. TMEJ is initiated by Polθ identifying the broken ends, aligning the two pieces of DNA, and annealing them together. This often leaves residual flaps of single stranded DNA ends, which is when Polδ enters to cut them off, allowing Polθ to initiate DNA synthesis to fill in gaps on the strands. The synthesis step is finally completed by Polδ, a more accurate and efficient polymerase than Polθ.

'What was so beautiful and kind of elegant about the whole discovery is that there are two different enzymes alternating between pathway steps and helping each other out,' said Dr Stroik.

The authors reported that the two enzymes are physically joined together.

Since DNA repair pathways are often hijacked by cancer cells to help them survive genome instability, the research could potentially inform drug developers to interrupt the pathway and kill cancer cells by disrupting its repair abilities.

'Now that we know more about this pathway, scientists could, in theory, produce a drug that could disrupt key pieces of the pathway in cancer cells, as opposed to using conventional chemotherapies that destroy healthy cells along with the cancer,' said Dr Stroik.

However, further studies need to be conducted to study the effect of TMEJ inhibition on healthy cells, since TMEJ also occurs in conventional DNA repair.