Investigating the Role of DNA Repair Protein in Cancer Therapy

Researchers from Scripps Research have made significant strides in understanding the function of a vital DNA repair protein known as polymerase theta (Pol-theta). This enzyme plays a crucial role in the body by repairing damaged DNA, a frequent occurrence that happens millions of times daily across various cells. However, cancer cells have been observed to exploit Pol-theta to evade normal repair mechanisms, which has been a focus of scientific investigation.

The team's recent findings, published in Nature Structural & Molecular Biology, detail the structural changes Pol-theta undergoes when it binds to damaged DNA strands. By capturing images of Pol-theta in its active state, the research offers new insights into the molecular interactions that contribute to various cancers.

Understanding the precise function of Pol-theta opens pathways for developing targeted cancer therapies. With a clearer understanding of how Pol-theta operates, scientists aim to design drugs that can inhibit its activity effectively. This is particularly important for cancers linked to BRCA1 or BRCA2 mutations, such as specific breast and ovarian cancers, which utilize Pol-theta's error-prone repair mechanism instead of more accurate pathways.

Previous studies had established the existence of Pol-theta in both tetrameric (four enzyme units) and dimeric (two enzyme units) forms, but the significance of these configurations was not fully understood until now. The current study utilized advanced cryo-electron microscopy techniques and biochemical analyses to reveal that Pol-theta switches to a dimeric form when it engages with broken DNA strands, a configuration that had not been observed before.

In its active state, Pol-theta initiates DNA repair through a two-step mechanism. Initially, it identifies matching sequences on the damaged strands, known as microhomologies. After locating a match, Pol-theta aligns the broken strands, enabling them to reconnect without requiring additional energy. This unique characteristic differentiates Pol-theta from other enzymes that typically need an energy boost to perform similar tasks.

Blocking this repair process could enhance the sensitivity of Pol-theta-dependent cancers to existing treatments. Given that healthy cells produce Pol-theta at low levels, targeting this enzyme could potentially spare normal tissues from damage while effectively attacking cancer cells that rely on it for survival. This is a significant advantage over traditional cancer therapies, which often affect both healthy and cancerous cells alike.

Clinical trials are underway for drugs designed to inhibit Pol-theta, although they currently need to be used alongside other treatments for maximum effectiveness. The findings from this study are expected to inform the development of more precise therapeutic options. Further research is also planned to investigate the reasons behind Pol-theta's dual forms and its interactions with other DNA repair enzymes, which may provide additional strategies for targeting BRCA-associated cancers.

In summary, the research on Pol-theta is paving the way for innovative cancer treatments that could selectively target malignant cells while minimizing harm to healthy ones.