Mammalian Polymerase Theta Promotes Alternative-NHEJ and Suppresses Recombination

By Pedro A. Mateos-Gómez, Fade Gong, Nidhi Nair, K. Miller, Eros Lazzerini-Denchi, Agnel Sfeir. Nature, 2015

691 citations recorded by the source corpus.

The alternative non-homologous end-joining (NHEJ) machinery facilitates several genomic rearrangements, some of which can lead to cellular transformation. This error-prone repair pathway is triggered upon telomere de-protection to promote the formation of deleterious chromosome end-to-end fusions. Using next-generation sequencing technology, here we show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres. Investigating the enzymatic activity responsible for the random insertions enabled us to identify polymerase theta (Polθ; encoded by Polq in mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq in mice results in increased rates of homology-directed repair, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we show that depletion of Polθ has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/c4323422b242941196364a83b9d84845eaa6fbd2

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Mark J. O'Connor

Citations in the corpus

Homologous recombination deficiency: Exploiting the fundamental vulnerability of ovarian cancer (2015, background): “Indeed, fill-in synthesis in alt-EJ is likely mediated by the Polθ polymerase, which is error-prone and likely produces point mutations, as well as random insertions and deletions (indels; refs.”
Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action (2016, background): “Although PARP trapping may be central to the mechanism of action of these inhibitors, it is also clear that PARP plays multiple roles in DNA repair, including the repair of the DSBs, and that inhibiting PARP during this process may also be an important component of cancer cell killing (15, 77).”
CRISPR/Cas Genome Editing and Precision Plant Breeding in Agriculture. (2019, background): “In mammalian cells, simultaneous knockout of PolQ and one of several genes that are essential for classical NHEJ (Ligase 4,Ku70,Ku80) resulted in 100% gene correction by HDR and no random integration of foreign DNA (105).”
Repair Pathway Choices and Consequences at the Double-Strand Break (2015, positive): “As the mutagenic alt-EJ and SSA pathways play backup roles for HR [49,73,93], and copy number aberrations in HR-deficient basal-like breast cancers promote the use of these error-prone pathways, repair through alt-EJ or SSA could account for the characteristic mutational spectra observed in all HR-d”
DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy (2021, background): “Furthermore, Polθ can indicate the microhomologous DNA ends to support the joining of DNA ends.(320) Moreover, the maximum activity of the alt-EJ pathway was observed in the G2 phase of the cell cycle.”