DNA polymerase theta (pol θ) is encoded in the genomes of many eukaryotes, 
though not in fungi. Pol θ is encoded by the POLQ gene in mammalian cells. The 
C-terminal third of the protein is a family A DNA polymerase with additional 
insertion elements relative to prokaryotic homologs. The N-terminal third is a 
helicase-like domain with DNA-dependent ATPase activity. Pol θ is important in 
the repair of genomic double-strand breaks (DSBs) from many sources. These 
include breaks formed by ionizing radiation and topoisomerase inhibitors, breaks 
arising at stalled DNA replication forks, breaks introduced during 
diversification steps of the mammalian immune system, and DSB induced by 
CRISPR-Cas9. Pol θ participates in a route of DSB repair termed "alternative 
end-joining" (altEJ). AltEJ is independent of the DNA binding Ku protein complex 
and requires DNA end resection. Pol θ is able to mediate joining of two resected 
3' ends harboring DNA sequence microhomology. "Signatures" of Pol θ action 
during altEJ are the frequent utilization of longer microhomologies, and the 
insertion of additional sequences at joining sites. The mechanism of end-joining 
employs the ability of Pol θ to tightly grasp a 3' terminus through unique 
contacts in the active site, allowing extension from minimally paired primers. 
Pol θ is involved in controlling the frequency of chromosome translocations and 
preserves genome integrity by limiting large deletions. It may also play a 
backup role in DNA base excision repair. POLQ is a member of a cluster of 
similarly upregulated genes that are strongly correlated with poor clinical 
outcome for breast cancer, ovarian cancer and other cancer types. Inhibition of 
pol θ is a compelling approach for combination therapy of radiosensitization.