Genome Protection by DNA Polymerase θ

Abstract

DNA polymerase θ (Pol θ) is a DNA repair enzyme widely conserved in animals and plants. Pol θ uses short DNA sequence homologies to initiate repair of double-strand breaks by theta-mediated end joining. The DNA polymerase domain of Pol θ is at the C terminus and is connected to an N-terminal DNA helicase–like domain by a central linker. Pol θ is crucial for maintenance of damaged genomes during development, protects DNA against extensive deletions, and limits loss of heterozygosity. The cost of using Pol θ for genome protection is that a few nucleotides are usually deleted or added at the repair site. Inactivation of Pol θ often enhances the sensitivity of cells to DNA strand–breaking chemicals and radiation. Since some homologous recombination–defective cancers depend on Pol θ for growth, inhibitors of Pol θ may be useful in treating such tumors. Expected final online publication date for the Annual Review of Genetics, Volume 56 is November 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

SCFcyclin F- EXO1 axis controls cell cycle dependent execution of double strand break repair

“…A key mediator of MMEJ is the DNA polymerase POLQ. Several POLQ inhibitors are being developed and are entering clinical trials as they demonstrate exciting anti-cancer potential 43 . Given that CCNF depletion- or EXO1 R842A mutation-mediated hyper-resection leads to defective MMEJ, exploiting the cyclin F-EXO1 pathway could be an alternative approach to POLQ inhibition to restrict MMEJ and, therefore, to sensitise cells to IR.…”

Multifaceted Nature of DNA Polymerase θ

“…Initially, it was suggested that Pol θ performs end trimming using the intrinsic endonuclease activity associated with the PD (repurposing of metal ions in the polymerase active site for endonucleolytic cleavage) [ 35 ]. However, in a further paper, an alternative explanation of the results was provided which made the authors doubt the existence of trimming endonuclease activity [ 5 ]. The PD structure lacks a potential endonuclease domain [ 11 ].…”

“…As it turned out, Pol θ cell functions are more diverse than previously expected. This unique enzyme is involved in a number of different DNA-related pathways reviewed in [ 4 , 5 , 6 , 7 , 8 ]. In this review, we discuss unique properties of Pol θ, its roles in the protection of genome stability and integrity as well as recent progress in studies of Pol θ as a target for cancer treatment.…”

Spontaneous regression of tumours. Possible cross reactivity of autoantibodies against carbonic anhydrase I

“…One of the candidates with strong possible cross reactivity could be the enzyme DNA polymerase theta (Polθ). The DNA polymerase Polθ has been described rather in detail 22–24 . From four established linear immune epitopes in CA I (DGLAV, NVGHS, SLKPI and SSEQL), the alignment with amino acid sequence of Polθ (https://www.uniprot.org/uniprotkb/O75417/entry#sequences) can be found in three of them: SLKPI, DGLAV and SSEQL.…”

“…The DNA polymerase Polθ has been described rather in detail. [22][23][24] From four established linear im- 25 The reverse transcriptase activity of Polθ has been shown in elegant experiments in Richard Pomerantz's lab. 26 Therefore, Polθ seems to be an ideal candidate for a cancer drug target.…”