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Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining

Abstract

Cellular pathways that repair chromosomal double-strand breaks (DSBs) have pivotal roles in cell growth, development and cancer. These DSB repair pathways have been the target of intensive investigation, but one pathway — alternative end joining (a-EJ) — has long resisted elucidation. In this Review, we highlight recent progress in our understanding of a-EJ, especially the assignment of DNA polymerase theta (Polθ) as the predominant mediator of a-EJ in most eukaryotes, and discuss a potential molecular mechanism by which Polθ-mediated end joining (TMEJ) occurs. We address possible cellular functions of TMEJ in resolving DSBs that are refractory to repair by non-homologous end joining (NHEJ), DSBs generated following replication fork collapse and DSBs present owing to stalling of repair by homologous recombination. We also discuss how these context-dependent cellular roles explain how TMEJ can both protect against and cause genome instability, and the emerging potential of Polθ as a therapeutic target in cancer.

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Fig. 1: DNA double-strand break repair pathways and microhomology use during end joining.
Fig. 2: Molecular mechanism of Polθ-mediated end joining.
Fig. 3: Biological roles of Polθ-mediated end joining.
Fig. 4: Regulation of Polθ-mediated end joining through end resection.
Fig. 5: Translation of Polθ inhibitors into the clinic.

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Acknowledgements

This work was supported by US NIH grants CA222092 and CA247773 to D.A.R. and G.P.G.

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Correspondence to Dale A. Ramsden or Gaorav P. Gupta.

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G.P.G. receives research funding from Breakpoint Therapeutics, which is developing inhibitors of polymerase-θ. D.A.R. has a materials transfer agreement with Artios Pharma, and is using an Artios Pharma compound that inhibits polymerase-θ for research purposes, with no financial compensation.

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Glossary

A-family polymerases

One of seven groupings of eukaryotic DNA polymerases, consisting in mammals of polymerase-γ, polymerase-ν and polymerase-θ.

Presynaptic filament

In homologous recombination, resected DNA ends bound by RAD51; a precursor to synapsis of the ends with a sister chromatid or homologous chromosome.

Non-allelic HR

Recombination between homologous sequences that are not allelic (for example, between repeat sequences on different chromosomes).

G-quadruplex

Stable secondary structures of DNA generated by guanine-rich sequences; can impede DNA replication and transcription.

Genomic scar

A recurring pattern of mutagenesis that can be attributed to a specific cause or DNA repair process.

Mitotic DNA synthesis

DNA replication stress-induced repair process that involves DNA synthesis during mitosis, possibly involving break-induced replication.

Chromothripsis

Clustered chromosomal rearrangements observed in cancer that involve shattering of a chromosome (portion) into many fragments, most likely during erroneous mitotic progression, followed by mutagenic rejoining of the fragments.

Telomere crisis

A stage of telomere erosion that is sufficient to cause chromosome instability and cell death.

T-DNA

‘Transfer DNA’ that is transferred from the plasmid genome of some tumour-inducing bacteria into the genome of a plant host.

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Ramsden, D.A., Carvajal-Garcia, J. & Gupta, G.P. Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining. Nat Rev Mol Cell Biol (2021). https://doi.org/10.1038/s41580-021-00405-2

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