UniProt release 2015_06
Published May 27, 2015
POLQ, a new target for cancer therapy?
DNA double-strand breaks (DSBs) are our worse cellular enemy, yet they do occur all the time, often accidentally, as a result of endogenous metabolic reactions and replication stress. They can also be induced by exogenous sources, like radiation or exposure of cells to DNA-damaging agents, or serve as intermediates in a number of programmed recombination events, during meiosis or assembly of immunoglobulins or T-cell receptors. Whatever their origin, DSBs are highly toxic to cells if not repaired, and if repaired incorrectly, they can cause deletions, translocations, and fusions in the DNA, which can have dramatic consequences.
The most frequently used mechanisms for DSB repair are homologous recombination (HR) and non-homologous end-joining (NHEJ), but alternative forms of end-joining exist, such as microhomology-mediated end-joining (MMEJ). HR is highly accurate and therefore important for preserving genome integrity. NHEJ results in small, less than 10 bp deletions. The most error-prone is MMEJ, which promotes inter- and intrachromosome rearrangements associated with relatively large DNA deletions (30-200 bp).
While NHEJ preferentially acts on ‘blunt-ended’ DNA breaks, HR is preceded by resection of DNA around the 5’-ends of the break. RAD51 proteins bind to the resulting 3’ single-stranded overhangs and help them to recognize complementary (homologous) DNA in another intact DNA helix. The overhangs then invade the homologous double-strand and use it as a template for repair. MMEJ also starts with DNA resected ends, but in this case it is DNA polymerase theta (POLQ) that directly binds them and enables short (2-6 bp) homologous DNA sequences in overhangs to form base pairs. The homology can be either terminal, or internal, as far as 5 nucleotides away from the 3’ terminus. Once homology has been found, each DNA strand is extended from the base-paired region using the opposing overhang as a template, and, in case of internal homology, the terminal unpaired regions are removed.
Normal cells tend to down-regulate POLQ. Cancer cells, which exhibit HR deficiency due to mutations in genes involved in HR repair, tend to up-regulate POLQ. This allows them to limit DNA damage and survive, although at the expense of genome integrity. In these cells, increased levels in POLQ will further inhibit HR, by binding to RAD51 proteins and preventing their accumulation at resected DNA ends.
Cytotoxic drugs used for cancer therapy promote DSBs in order to overwhelm DNA repair mechanisms and induce cell death. Could the use of POLQ inhibitors, alone or in combination with other DNA damaging drugs, improve the treatment of HR-deficient tumors? It’s too early to tell, but preliminary results suggest that it is worth investigating. Indeed, knockdown of POLQ in HR-deficient cells reduces cell survival following treatment with cisplatin or mitomycin C, and human tumor cells expressing shRNA against both FANCD2 (HR knockdown) and POLQ (MMEJ knockdown) do not grow in mice.
At the beginning of this year, POLQ was in the spotlight thanks to 3 very interesting publications, which shed light on its role and mode of action. UniProtKB/Swiss-Prot POLQ entries have been updated accordingly and are publicly available as of this release.