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Image: The structure of DNA polymerase, which fixes double-stranded breaks (on top)
in DNA by connecting hanging single-stranded ends and catalyzing DNA synthesis.
Researchers at Rice University and St.
Jude Children's Research Hospital studied the enzyme's role in microhomologous-mediating terminal ligation and found it could be a promising target for precision cancer therapy
.
Researchers from Rice University and St.
Jude Children's Research Hospital took a closer look at one way cells repair broken DNA strands and found details that could help make a particular enzyme a promising target for precision cancer treatments
.
Like tinkering tires, DNA polymerase (aka Pol) works to repair double-stranded breaks in DNA, connect hanging single-stranded ends, and catalyze DNA synthesis, a process known as microhomology-mediated end ligation (MMEJ).
MMEJ complements two other processes for repairing DNA double-strand breaks – homologous recombination and non-homologous end ligation – but with lower fidelity because Pol theta is prone to mutation, insertion and deletion errors
.
But here's where it excels: MMEJ needs Pol theta to fix the double-strand.
A new study published in the journal Nucleic Acid Research by researchers at Rice University and St.
Jude University is the first to reveal the structural basis of Pol theta-mediated MMEJ, showing how its unique insertion loop helps stabilize short DNA binding
when preparing sites for MMEJ repair.
Yang Gao, Assistant Professor of Biological Sciences at Rice, Ji Sun, Assistant Member of the Department of Structural Biology, and Chuxuan Li and St.
Rice's Postdoctoral Fellows.
Jude's Hanwen Zhu led the study
.
Gao, a cancer researcher at the Texas Cancer Prevention and Research Institute (CPRIT) who studies the mechanisms of DNA replication, said: "When DNA breaks, it is very dangerous for the cell, and it must repair it
immediately.
" "A break kills the cell, and the cell doesn't want to die, especially the cancer cell
.
"One of the most common cases is that the patient has a BRCA1 or BRCA2 mutation," he said
.
When healthy, these genes express DNA repair proteins, but mutations can trigger breast cancer
.
"When there is a problem with these genes in patients, they cannot be repaired
through the homologous recombination pathway.
They have to go the other way
.
"8 years ago people found out that when they knocked out Pol theta in normal cells, there would be no problem
," Gao said.
"But if knockout of this protein occurs in cells with BRCA1 or BRCA2 mutations, these defects can be fatal
.
" This makes it a very promising drug target
.
Pol theta inhibitors do not harm normal cells, only cancer cells
.
”
Clinical trials of such treatments are underway based on studies from other labs, he said, but the study in the Rice University lab adds details
about the mechanism.
While the experiments in the new paper are about proteins extracted from Asian sea bass, work continues on the human version
.
