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Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells
- Source :
- Biology Open, Vol 5, Iss 10, Pp 1485-1492 (2016), Biology Open
- Publication Year :
- 2016
- Publisher :
- The Company of Biologists, 2016.
-
Abstract
- 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.<br />Summary: Our work suggests that Polθ upregulation may be crucial for homologous recombination (HR)-proficient cells to better tolerate DNA replication stress, as part of a global gene deregulation response, including HR genes.
- Subjects :
- 0301 basic medicine
Genetics and Molecular Biology (all)
Synthetic lethality
DNA polymerase
QH301-705.5
Science
DNA Polymerase Theta
Polθ
Biochemistry
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
chemistry.chemical_compound
DNA polymerase theta
DNA Replication Timing
High-throughput screen
Biology (General)
Gene
biology
DNA replication
High-Throughput screen
Biochemistry, Genetics and Molecular Biology (all)
Agricultural and Biological Sciences (all)
Molecular biology
030104 developmental biology
chemistry
Cancer cell
biology.protein
Cancer research
General Agricultural and Biological Sciences
Homologous recombination
DNA
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 20466390
- Volume :
- 5
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Biology Open
- Accession number :
- edsair.doi.dedup.....9471167856f80d80fa63489cf6c51a35