Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells.
DNA polymerase theta (Polθ) is a specialized A-family DNA polymerase that functions in processes such as translesion synthesis (TLS), DNA double-strand break repair and DNA replication timing. Overexpression of POLQ, the gene encoding Polθ, is a prognostic marker for an adverse outcome in a wide range of human cancers. While increased Polθ dosage was recently suggested to promote survival of homologous recombination (HR)-deficient cancer cells, it remains unclear whether POLQ overexpression could be also beneficial to HR-proficient cancer cells. By performing a short interfering (si)RNA screen in which genes encoding druggable proteins were knocked down in Polθ-overexpressing cells as a means to uncover genetic vulnerabilities associated with POLQ overexpression, we could not identify genes that were essential for viability in Polθ-overexpressing cells in normal growth conditions. We also showed that, upon external DNA replication stress, Polθ expression promotes cell survival and limits genetic instability. Finally, we report that POLQ expression correlates with the expression of a set of HR genes in breast, lung and colorectal cancers. Collectively, our data suggest that Polθ upregulation, besides its importance for survival of HR-deficient cancer cells, may be crucial also for HR-proficient cells to better tolerate DNA replication stress, as part of a global gene deregulation response, including HR genes.
UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), 2 Avenue Hubert, Curien CS 53717, Toulouse 31037, Cedex 1, France UMR1037, CRCT, Université Toulouse, III-Paul Sabatier, Toulouse F-31000, France Equipe Labellisée Ligue Contre le Cancer, Toulouse F-31000, France.
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Goullet de Rugy
The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5.
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Bashkurov
The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5 Department of Agricultural, Food and Environmental Sciences, University of Perugia, Perugia 06121-06135, Italy.
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Datti
UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), 2 Avenue Hubert, Curien CS 53717, Toulouse 31037, Cedex 1, France UMR1037, CRCT, Université Toulouse, III-Paul Sabatier, Toulouse F-31000, France Equipe Labellisée Ligue Contre le Cancer, Toulouse F-31000, France.
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Betous
UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), 2 Avenue Hubert, Curien CS 53717, Toulouse 31037, Cedex 1, France UMR1037, CRCT, Université Toulouse, III-Paul Sabatier, Toulouse F-31000, France Equipe Labellisée Ligue Contre le Cancer, Toulouse F-31000, France.
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Guitton-Sert
UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), 2 Avenue Hubert, Curien CS 53717, Toulouse 31037, Cedex 1, France UMR1037, CRCT, Université Toulouse, III-Paul Sabatier, Toulouse F-31000, France Equipe Labellisée Ligue Contre le Cancer, Toulouse F-31000, France.
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Cazaux
The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5.
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Durocher
UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), 2 Avenue Hubert, Curien CS 53717, Toulouse 31037, Cedex 1, France UMR1037, CRCT, Université Toulouse, III-Paul Sabatier, Toulouse F-31000, France Equipe Labellisée Ligue Contre le Cancer, Toulouse F-31000, France Jean-Sebastien.hoffmann@inserm.fr.
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0000-0003-2222-354X
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Hoffmann
DNA polymerase theta; High­-throughput screen; Polθ; Synthetic lethality