Cell Rep: Blocks DNA production by targeting the enzyme POLtheta in cancer therapy

In a recent study, researchers from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the team of Joanna Loizou of the Medical University of Vienna investigated the POLΘ enzyme and its role
in DNA repair.
Inhibition of Boll Θ represents a new approach to developing specific therapies, particularly for patients with
BRCA1 mutations.
The study, published in Cell Reports, is the first to show that POLΘ fills the single-stranded DNA gap that appears excessively in the background of BRCA1-deficient genes, thus demonstrating its important role
in keeping BRCA1-deficient cells alive.

(Vienna, November 17, 2022) A key gene that causes breast and ovarian cancer is BRCA1 (breast cancer gene 1), which plays an important role
in the body's DNA repair machinery.
Once BRCA1 is mutated, it can cause cancer
.
According to the Center for Familial Breast and Ovarian Cancer at Vienna General Hospital, if the BRCA1 or BRCA2 genes are mutated, the likelihood of developing breast and ovarian cancer increases to 85 percent and 53 percent
, respectively.
While mutations in BRCA1 and BRCA2 support uncontrolled cell growth, these mutations can also lead to instability
of the genetic material within the cell.
Therefore, these types of cancer cells rely on other repair mechanisms to compensate for these defects
.
The dependence of cells with mutated BRCA1 or BRCA2 genes on other genes can be considered Achilles' heel for cancer cells, because targeting other DNA repair genes can produce a synthetically lethal relationship
.
Joanna Loizou, associate professor at the Comprehensive Cancer Center at the Medical University of Vienna and former leader of the research team at CeMM, explains: "Synthetic lethality, as a therapeutic concept for the treatment of breast and ovarian cancer, very clearly prevents cancer cells from dividing while leaving healthy cells unaffected
.
This treatment concept has advantages
over traditional chemotherapy.
”

POLΘ fills the gap in single-stranded DNA

First authors Anna Schlempf and Sarah Bernardo focused on the enzyme POLΘ (DNA polymerase), which is part of the cell's
DNA repair mechanism and whose loss is synthetically fatal with BRCA1 mutations.
POLΘ has been shown to play a key role
in repairing DNA double-strand breaks.
In their study, published in Cell Reports, the two researchers showed that in addition to this effect, POLΘ also fills in the single-stranded DNA gap
created during DNA replication.
Boll Θ
.
"We demonstrate the function of POLΘ, which previously described, which gives us a better understanding of its DNA repair mechanism and the important role
it plays in DNA replication.
" By inhibiting POLΘ with the drug, we disrupt the stability of the genetic material of BRCA1-mutant cancer cells, further slowing cell division and stopping growth," Schrempf explains
.

By inhibiting PARP, a protein similar to POLΘ, a similar approach
has been successfully employed in cancer treatment.
PARP has a synthetically lethal relationship
with BRCA1-deficient cells.
In clinical applications, PARP-based therapy has been found to be very successful, but patients have also been found to develop drug-resistant tumors
.
"This makes it even more important
to understand the process of our DNA repair mechanisms in detail and identify other potential therapeutic avenues," Loizou said.