Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

Article  CAS  PubMed  Google Scholar 

Scully, R., Panday, A., Elango, R. & Willis, N. A. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat. Rev. Mol. Cell Biol. 20, 698–714 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ceccaldi, R., Rondinelli, B. & D’Andrea, A. D. Repair pathway choices and consequences at the double-strand break. Trends Cell Biol. 26, 52–64 (2016).

Article  CAS  PubMed  Google Scholar 

Ramsden, D. A., Carvajal-Garcia, J. & Gupta, G. P. Mechanism, cellular functions and cancer roles of polymerase-θ-mediated DNA end joining. Nat. Rev. Mol. Cell Biol. 23, 125–140 (2022).

Article  CAS  PubMed  Google Scholar 

Wood, R. D. & Doublié, S. DNA polymerase θ (POLQ), double-strand break repair, and cancer. DNA Repair 44, 22–32 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chan, S. H., Yu, A. M. & McVey, M. Dual roles for DNA polymerase θ in alternative end-joining repair of double-strand breaks in Drosophila. PLoS Genet. 6, e1001005 (2010).

Article  PubMed  PubMed Central  Google Scholar 

Yousefzadeh, M. J. et al. Mechanism of suppression of chromosomal instability by DNA polymerase POLQ. PLoS Genet. 10, e1004654 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Mateos-Gomez, P. A. et al. Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination. Nature 518, 254–257 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ceccaldi, R. et al. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature 518, 258–262 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wyatt, D. W. et al. Essential roles for polymerase θ-mediated end joining in the repair of chromosome breaks. Mol. Cell 63, 662–673 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zatreanu, D. et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat. Commun. 12, 3636 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhou, J. et al. A first-in-class polymerase θ inhibitor selectively targets homologous-recombination-deficient tumors. Nat. Cancer 2, 598–610 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Study of orally administered MOMA-313 in participants with advanced or metastatic solid tumors (NCT06545942). https://clinicaltrials.gov/study/NCT06545942 (2024).

A study of ART4215 for the treatment of advanced or metastatic solid tumors (NCT04991480). https://clinicaltrials.gov/study/NCT04991480 (2021).

A study to investigate the safety, tolerability, pharmacokinetics (PK), and preliminary anticancer activity of GSK4524101 alone or with niraparib in participants with solid tumors (NCT06077877). https://clinicaltrials.gov/study/NCT06077877 (2023).

Seki, M., Marini, F. & Wood, R. D. POLQ (Pol θ), a DNA polymerase and DNA-dependent ATPase in human cells. Nucleic Acids Res. 31, 6117–6126 (2003).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Carvajal-Garcia, J. et al. Mechanistic basis for microhomology identification and genome scarring by polymerase θ. Proc. Natl Acad. Sci. USA 117, 8476–8485 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

He, P. & Yang, W. Template and primer requirements for DNA Pol θ-mediated end joining. Proc. Natl Acad. Sci. USA 115, 7747–7752 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Luedeman, M. E. et al. Poly(ADP) ribose polymerase promotes DNA polymerase θ-mediated end joining by activation of end resection. Nat. Commun. 13, 4547 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kent, T., Chandramouly, G., McDevitt, S. M., Ozdemir, A. Y. & Pomerantz, R. T. Mechanism of microhomology-mediated end-joining promoted by human DNA polymerase θ. Nat. Struct. Mol. Biol. 22, 230–237 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fijen, C. et al. Sequential requirements for distinct Polθ domains during theta-mediated end joining. Mol. Cell 84, 1460–1474 (2024).

Article  CAS  PubMed  Google Scholar 

Black, S. J. et al. Molecular basis of microhomology-mediated end-joining by purified full-length Polθ. Nat. Commun. 10, 4423 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mateos-Gomez, P. A. et al. The helicase domain of Polθ counteracts RPA to promote alt-NHEJ. Nat. Struct. Mol. Biol. 24, 1116–1123 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schaub, J. M., Soniat, M. M. & Finkelstein, I. J. Polymerase θ-helicase promotes end joining by stripping single-stranded DNA-binding proteins and bridging DNA ends. Nucleic Acids Res. 50, 3911–3921 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Newman, J. A., Cooper, C. D. O., Aitkenhead, H. & Gileadi, O. Structure of the helicase domain of DNA polymerase θ reveals a possible role in the microhomology-mediated end-joining pathway. Structure 23, 2319–2330 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ozdemir, A. Y., Rusanov, T., Kent, T., Siddique, L. A. & Pomerantz, R. T. Polymerase θ-helicase efficiently unwinds DNA and RNA–DNA hybrids. J. Biol. Chem. 293, 5259–5269 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Guo, H. et al. Cryo-EM structure of DNA polymerase θ helicase domain in complex with inhibitor novobiocin. Preprint at bioRxiv https://doi.org/10.1101/2023.01.20.524915 (2023).

Abramson, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493–500 (2024).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Büttner, K., Nehring, S. & Hopfner, K.-P. Structural basis for DNA duplex separation by a superfamily-2 helicase. Nat. Struct. Mol. Biol. 14, 647–652 (2007).

Article  PubMed  Google Scholar 

Richards, J. D. et al. Structure of the DNA repair helicase Hel308 reveals DNA binding and autoinhibitory domains. J. Biol. Chem. 283, 5118–5126 (2008).

Article  CAS  PubMed  Google Scholar 

Gyimesi, M., Sarlós, K. & Kovács, M. Processive translocation mechanism of the human Bloom’s syndrome helicase along single-stranded DNA. Nucleic Acids Res. 38, 4404–4414 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schrempf, A., Slyskova, J. & Loizou, J. I. Targeting the DNA repair enzyme polymerase θ in cancer therapy. Trends Cancer 7, 98–111 (2021).

Article  CAS  PubMed