Rosa Rubicondior: Malevolent Design - How Creationism's Divine Malevolence Co-opted A Solutions For It's Own Incompetence, To Ensure Cancers Survive

How a crucial DNA repair protein works—and what it means for cancer treatment | Scripps Research

According to creationist mythology, once upon a time a magic creator created animal life complete with DNA which needs to be replicated every time a cell divides for growth and/or repair.

Unfortunately, the process it designed to make this happen wasn't very well designed, so the resulting DNA is often broken or faulty. DNA can be broken in a number of ways, all of which could have been avoided by a more robust design, which should have been within the capabilities of an omniscient deity, capable of creating living organisms ex nihilo:

DNA double-strand breaks can occur in multiple phases of the cell cycle, not just mitosis. While replication stress is a major endogenous source, environmental factors like radiation, chemicals, and viruses can also introduce DSBs. Cells rely on homologous recombination (HR), non-homologous end joining (NHEJ), and alternative end joining (alt-EJ) to repair these breaks, though error-prone pathways like Pol θ-mediated repair contribute to mutagenesis.

Then, in a method typical of creationism's incompetent designer, which in every respect resembles a mindless utilitarian natural process, proceeding without a plan and settling for suboptimal solutions, it added yet another layer of complexity as a work-around for its failure, and designed the enzyme, polymerase θ (Pol-θ), which searches the DNA looking for faults. Unfortunately, due to suboptimal design, this too fails and produces cancers.

What information do you have on the enzyme polymerase θ? Polymerase θ (Pol θ), encoded by the POLQ gene, is a specialized DNA polymerase with both polymerase and helicase activities. It plays a crucial role in alternative end-joining (alt-EJ), also known as microhomology-mediated end joining (MMEJ), a repair pathway for double-strand breaks (DSBs) in DNA. Unlike high-fidelity polymerases, Pol θ is error-prone and tends to introduce mutations and small insertions/deletions during repair.

Functions of Polymerase θ:

Alternative End-Joining (alt-EJ/MMEJ)

Pol θ is essential for a mutagenic form of DSB repair that relies on microhomology at the break site.
It promotes DNA end resection and fills in short gaps, leading to small deletions or insertions.
This pathway is used when classical non-homologous end joining (NHEJ) and homologous recombination (HR) are unavailable or inefficient.

Translesion Synthesis (TLS) Activity

Pol θ can bypass certain DNA lesions, though its role in TLS is less prominent compared to polymerases like Pol η or Pol κ.

Suppression of Homologous Recombination (HR)

By promoting alt-EJ, Pol θ prevents cells from using HR, which is more accurate but also requires extensive sequence homology.

Tumorigenesis and Cancer Therapy Resistance

Cancer cells with BRCA1/2 deficiencies (which impair HR) rely heavily on Pol θ for DNA repair.
Its activity contributes to genomic instability, increasing mutational burdens in cancer.
Targeting Pol θ is a potential therapeutic strategy for cancers with HR deficiencies (synthetic lethality approach).

Interplay with Other Repair Pathways

Works alongside proteins like PARP1, LIG3, and XRCC1 in alt-EJ.
Competes with classical NHEJ (Ku70/80, DNA-PK, and Ligase IV).

Structure and Mechanism:

C-terminal polymerase domain: Exhibits low fidelity and can extend mismatched bases.
N-terminal helicase-like domain: Required for unwinding DNA and mediating end-joining.
Flexible linker region: Helps coordinate polymerase and helicase functions.
Relevance in Evolution and Disease:

Found in vertebrates and some invertebrates, suggesting an evolutionary adaptation for DNA repair.
Its overexpression is linked to tumour progression, making it a biomarker for certain cancers.
Targeting Pol θ with inhibitors (e.g., for HR-deficient cancers) is an emerging area of cancer treatment research.
Would you like details on Pol θ inhibitors, its evolutionary origins, or more about its role in cancer?

Yes, both please.

Evolutionary Origins of Polymerase θ (Pol θ)

Polymerase θ (POLQ) belongs to the A-family of DNA polymerases, which includes high-fidelity replicative polymerases like DNA polymerase γ (mitochondrial) and polymerases involved in DNA repair. However, Pol θ has diverged significantly from its high-fidelity relatives, acquiring both polymerase and helicase activities, which is a rare feature among DNA polymerases.

Evolutionary Conservation and Distribution

Pol θ is found in most vertebrates and some invertebrates, suggesting an ancient origin.
It is notably absent in fungi and bacteria, indicating that other repair mechanisms compensate in these organisms.
The presence of Pol θ in insects (e.g., Drosophila) and nematodes (C. elegans) suggests it evolved early in metazoan evolution.

Role in Evolutionary Adaptation

Pol θ contributes to genomic plasticity by introducing mutations through its error-prone repair mechanism.
In organisms with reduced homologous recombination (HR) capacity, Pol θ provides an alternative means of repairing double-strand breaks (DSBs).
The trade-off is increased mutagenesis, which may have influenced cancer susceptibility in higher organisms.

Relationship to Other Polymerases

Phylogenetic analyses suggest Pol θ evolved from an ancestral DNA polymerase A family member, likely through domain fusion events that added helicase-like functions.
Its helicase activity is unique within the polymerase A family, reinforcing its role in microhomology-mediated end joining (MMEJ).

Pol θ in Cancer and Therapeutic Targeting

Because Pol θ promotes error-prone repair, it is strongly associated with tumorigenesis, especially in cancers with homologous recombination (HR) deficiencies, such as BRCA1/2-mutant breast and ovarian cancers.

Pol θ in Cancer

Tumours with defective HR pathways (e.g., BRCA-mutant cancers) become highly dependent on Pol θ for survival.
Pol θ overexpression is found in many cancers, including:

Breast and ovarian cancers
Lung cancer
Glioblastoma
Colorectal cancer

High Pol θ expression correlates with poor prognosis due to its role in genomic instability.

Synthetic Lethality and Cancer Therapy

Targeting Pol θ is an emerging anti-cancer strategy, particularly in BRCA-deficient tumours that already struggle with DNA repair.
Synthetic lethality approach: If both HR and Pol θ are inhibited, cancer cells accumulate fatal DNA damage and die, while normal cells (which retain HR) survive.

Pol θ Inhibitors Under Development

Several small-molecule inhibitors of Pol θ have been developed, aiming to exploit this synthetic lethality:

ART558

A promising Pol θ polymerase inhibitor.
Effective against BRCA-mutant cancers by blocking alternative end-joining.
In preclinical testing, shows synergy with PARP inhibitors (e.g., olaparib).

RAD51 inhibitors in combination with Pol θ inhibitors

Blocking both Pol θ and HR proteins like RAD51 further sensitizes tumours.

PARP Inhibitors and Pol θ Dual Targeting

Since both PARP1 and Pol θ function in alt-EJ, inhibiting them together enhances cancer cell death.
Clinical trials are exploring this dual inhibition strategy.

Summary

Evolution: Pol θ evolved from an ancient polymerase A family member, gaining helicase activity and a role in mutagenic DNA repair.
Role in Cancer: Overexpressed in many tumours, it promotes genomic instability.
Therapeutic Target: Synthetic lethality approaches using Pol θ inhibitors (like ART558) alongside PARP inhibitors show promise in BRCA-deficient cancers.

What was not known until now was how this enzyme works and particularly what role it plays in cancer, other than causing it.

Now a group of researchers at the Scripps Institute, La Jolla, California, USA have captured images of Pol θ in action, revealing details of the molecular processes that cause cancers. Their findings were published in Nature Structural & Molecular Biology and are explained in a Scripps Institute News release:

How a crucial DNA repair protein works—and what it means for cancer treatment
New structural blueprint is key for better targeting cancer cells, particularly those with BRCA1 and 2 mutations.
DNA repair proteins act like the body’s editors, constantly finding and reversing damage to our genetic code. Researchers have long struggled to understand how cancer cells hijack one of these proteins—called polymerase theta (Pol-theta)—for their own survival. But scientists at Scripps Research have now captured the first detailed images of Pol-theta in action, revealing the molecular processes responsible for a range of cancers.

The findings, published in Nature Structural & Molecular Biology on February 28, 2025, illuminate how Pol-theta undergoes a major structural rearrangement when it binds to broken DNA strands. By unveiling Pol-theta’s DNA-bound structure—its active state—the study provides a blueprint for designing more effective cancer drugs.

We now have a much clearer picture of how Pol-theta works, which will enable us to block its activity more precisely.

Professor Gabriel C. Lander, senior author
Department of Integrative Structural and Computational Biology
Scripps Research, La Jolla, CA, USA.

Technically, Pol-theta is an enzyme—a type of protein that speeds up chemical reactions, including those related to cell repair. DNA damage is a constant problem for cells, occurring millions of times per day collectively throughout our bodies. Cells normally use highly accurate mechanisms to fix these breaks, but some cancers—particularly those arising from BRCA1 or BRCA2 mutations, such as certain breast and ovarian cancers—lack this function. Instead, they depend on a more error-prone method, controlled by Pol-theta.
Pol-theta is an important target, and many pharmaceutical companies see it as a promising way to treat cancers that have defective DNA repair pathways. What’s been missing is how Pol-theta actually engages DNA, which is essential for drug development.

Dr. Christopher J. Zerio, first author
Department of Integrative Structural and Computational Biology
Scripps Research, La Jolla, CA, USA.

Although previous studies have mapped parts of Pol-theta’s structure, the enzyme’s interactions with DNA weren’t well understood.

Prior research has shown that Pol-theta exists in two forms: a tetramer (four copies of the enzyme) and a dimer (two copies). But why or how Pol-theta changed between these forms was unknown.

Before this study, Pol-theta’s structure had only been captured in an inactive state, leaving a major knowledge gap regarding how the enzyme interacts with DNA. It was like trying to determine how a bee accesses nectar when all you’ve ever seen is a closed flower.

You know the interaction must happen, but without seeing it, the mechanism remains a mystery.

Professor Gabriel C. Lander.

Using cryo-electron microscopy and biochemical experiments, the team made a surprising discovery while capturing Pol-theta in the act of repairing DNA: Whenever Pol-theta bound to broken strands, it consistently switched from the tetrameric to a never-before-seen dimeric configuration.

Once in its active state, Pol-theta repairs DNA using a two-step process: First, the enzyme searches for small matching sequences called “microhomologies” on broken strands. Once a matching sequence is found, Pol-theta holds the broken DNA strands together so that they can be stitched together—without needing extra energy. Most enzymes require an energy boost to function, but Pol-theta relies on the natural attraction between matching DNA sequences, allowing them to snap into place on their own.

If we can block this process, we could make Pol-theta-dependent cancers much more sensitive to treatment.

Dr. Christopher J. Zerio.

Importantly, Pol-theta is produced at low levels in healthy cells, making it a promising target for cancer therapies. Unlike cancer cells, which depend on Pol-theta as a workaround for defective repair pathways, healthy ones rely on more accurate repair mechanisms that require energy—ensuring more precise DNA repair. Because healthy cells don’t need Pol-theta for survival, blocking the enzyme’s activity likely won’t cause widespread damage to healthy tissue.

Most cancer drugs target proteins that are also needed by healthy cells. Specifically targeting Pol-theta should only kill cancer cells, lowering the chance of side effects during therapy. We also want to understand why Pol-theta exists in its tetrameric form and how it interacts with other DNA repair enzymes. Such insights could lead to new ways of targeting BRCA-associated cancers.

Professor Gabriel C. Lander.

Drugs that inhibit Pol-theta are already in clinical trials, but they currently must be combined with other therapies to work effectively. While this study could inform more precise drug development, further research may reveal other roles the enzyme may play in cellular functions.
In addition to Lander and Zerio, authors of the study, “Human polymerase θ helicase positions DNA microhomologies for double-strand break repair,” include Yonghong Bai, Brian A. Sosa-Alvarado and Timothy Guzi of MOMA Therapeutics.

Abstract
DNA double-strand breaks occur daily in all human cells and must be repaired with high fidelity to minimize genomic instability. Deficiencies in high-fidelity DNA repair by homologous recombination lead to dependence on DNA polymerase θ, which identifies DNA microhomologies in 3′ single-stranded DNA overhangs and anneals them to initiate error-prone double-strand break repair. The resulting genomic instability is associated with numerous cancers, thereby making this polymerase an attractive therapeutic target. However, despite the biomedical importance of polymerase θ, the molecular details of how it initiates DNA break repair remain unclear. Here, we present cryo-electron microscopy structures of the polymerase θ helicase domain bound to microhomology-containing DNA, revealing DNA-induced rearrangements of the helicase that enable DNA repair. Our structures show that DNA-bound helicase dimers facilitate a microhomology search that positions 3′ single-stranded DNA ends in proximity to align complementary bases and anneal DNA microhomology. We characterize the molecular determinants that enable the helicase domain of polymerase θ to identify and pair DNA microhomologies to initiate mutagenic DNA repair, thereby providing insight into potentially targetable interactions for therapeutic interventions.

Zerio, Christopher J.; Bai, Yonghong; Sosa-Alvarado, Brian A.; Guzi, Timothy; Lander, Gabriel C.
Human polymerase θ helicase positions DNA microhomologies for double-strand break repair
Nature Structural & Molecular Biology (2025) DOI: 10.1038/s41594-025-01514-8.

© 2025 Springer Nature Ltd.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.

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