Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells.
T Goullet de RugyM BashkurovA DattiR BetousL Guitton-SertC CazauxD DurocherJean-Sebastien HoffmannPublished in: Biology open (2016)
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.
Keyphrases
- genome wide
- induced apoptosis
- poor prognosis
- genome wide identification
- dna damage
- cell cycle arrest
- cell proliferation
- dna repair
- copy number
- circulating tumor
- transcription factor
- single molecule
- endoplasmic reticulum stress
- cell free
- bioinformatics analysis
- signaling pathway
- long non coding rna
- emergency department
- palliative care
- high throughput
- binding protein
- cell death
- working memory
- young adults
- big data
- heat stress
- induced pluripotent stem cells