by ecancer reporter Janet Fricker

DNA polymerase offers novel druggable target DNA polymerase has been identified as a potential new therapeutic target for the treatment of certain cancers in two separate papers published online in Nature this week.

The repair of double-strand breaks in DNA is crucial for life, and can proceed by several mechanisms.

It is known that DNA-repair systems are deficient in many types of cancer, leading to the suggestion that inhibition of alternative repair pathways that compensate when the predominant mechanisms are impaired might offer a new approach for killing cancer cells.

In the first study Alan D’Andrea and colleagues, from Harvard Medical School, Boston, screened polymerase activity and polymerase gene expression profiles in a large number of cancers.¹

They showed that DNA Polymerase θ (Polθ) is over expressed in epithelial ovarian cancers (EOCs) and other tumours with homologous recombination (HR) defects.

The team went on to show that knockdown of Polθ in HR-proficient cells up regulates HR activity and RAD51 nucleofilament assembly; while knock-down of Polθ in HR-deficient EOCs enhances cell death.

“Our results reveal a synthetic lethal relationship between the HR pathway and Polθ mediated repair in EOCs and identify Polθ as a novel druggable target for cancer therapy,” write the authors.

In the second study Agnel Sfeir and colleagues, from New York University, explored the nature of DNA sequences at the junctions of two fused telomeres (repetitive DNA sequences capping the end of chromosomes).²

When the team sequenced mouse telomere fusion junctions in a non-homologous endjoining (NHEJ) deficient system, they observed seemingly random permuted sequences attributable to micro-homology-mediated end-joining (MMEJ) and that the enzyme Polθ promoted this process in mammalian cells.

When the authors reduced Polθ levels in the HR deficient mouse cells harbouring mutations in either of the breast cancer susceptibility genes brca1 or brca2 they found this greatly exacerbated chromosomal aberrancies and reduced the ability of cells to survive.

Such results, say the authors, suggests that Polθ-mediated MMEJ was compensating for the loss of HR.

“Our findings that cells with compromised HDR activity depend on this mutagenic polymerase for survival establish a rationale for the development of Polθ-targeted approaches for cancer treatment,” write the authors.

In an accompanying ‘News & Views’ article ³Nam Woo Cho and Roger A Greenberg, from the University of Pennsylvania, Philadelphia, write, “The …papers provide a beautiful illustration of how the multifunctional DNA-repair toolkit is coordinated to faithfully preserve genome integrity. They also reveal how cancer cells may thrive through increased usage of error prone repair pathways – a strategy that enables cellular survival by limiting the accumulation of persistent DNA damage, but at the expense of genome integrity. Understanding the mechanisms involved opens up targets for anticancer drug research.”

References

1. R Ceccaldi, J C Liu, R Amunugama, et al. Homologous-recombination-deficient tumours are dependent on Po1θ-mediated repair. Nature.

2. P A Mateos-Gomez, F Gong, N Nair, et al. Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination. Nature.

3. N Woo Cho & R A Greenberg. Familiar ends with alternative endings. Nature.