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Updated: May 4, 2026
Evaluating In Vitro DNA Damage Using Comet Assay
Published on: October 11, 2017
Glioblastoma cells containing mutations in the cohesin component STAG2 are sensitive to PARP inhibition
Melanie L Bailey1, Nigel J O'Neil, Derek M van Pel
1Corresponding Author: Philip Hieter, Michael Smith Laboratories, 2185 East Mall, Room 323, University of British Columbia, Vancouver, British Columbia, Canada V6T1Z4. hieter@msl.ubc.ca.
Abstract:
Recent data have identified STAG2, a core subunit of the multifunctional cohesin complex, as a highly recurrently mutated gene in several types of cancer. We sought to identify a therapeutic strategy to selectively target cancer cells harboring inactivating mutations of STAG2 using two independent pairs of isogenic glioblastoma cell lines containing either an endogenous mutant STAG2 allele or a wild-type STAG2 allele restored by homologous recombination. We find that mutations in STAG2 are associated with significantly increased sensitivity to inhibitors of the DNA repair enzyme PARP. STAG2-mutated, PARP-inhibited cells accumulated in G2 phase and had a higher percentage of micronuclei, fragmented nuclei, and chromatin bridges compared with wild-type STAG2 cells. We also observed more 53BP1 foci in STAG2-mutated glioblastoma cells, suggesting that these cells have defects in DNA repair. Furthermore, cells with mutations in STAG2 were more sensitive than cells with wild-type STAG2 when PARP inhibitors were used in combination with DNA-damaging agents. These data suggest that PARP is a potential target for tumors harboring inactivating mutations in STAG2, and strongly recommend that STAG2 status be determined and correlated with therapeutic response to PARP inhibitors, both prospectively and retrospectively, in clinical trials.
Insights
Cancer cells with STAG2 mutations are more sensitive to PARP inhibitors, a DNA repair enzyme. This suggests targeting PARP could be a viable therapeutic strategy for STAG2-mutated tumors.
Area of Science:
- Cancer Biology
- Molecular Oncology
- Genetics
Background:
- STAG2 is a core subunit of the cohesin complex and is frequently mutated in various cancers.
- Inactivating STAG2 mutations are implicated in cancer development and progression.
Purpose of the Study:
- To identify a targeted therapeutic strategy for cancer cells with inactivating STAG2 mutations.
- To investigate the sensitivity of STAG2-mutated cells to PARP inhibitors.
Main Methods:
- Utilized isogenic glioblastoma cell lines with wild-type and mutant STAG2 alleles.
- Assessed cell cycle progression, DNA damage markers (micronuclei, chromatin bridges, 53BP1 foci), and sensitivity to PARP inhibitors.
- Evaluated combination therapy with PARP inhibitors and DNA-damaging agents.
Main Results:
- STAG2-mutated cells exhibited significantly increased sensitivity to PARP inhibitors.
- PARP inhibition led to G2 cell cycle arrest, increased DNA damage, and impaired DNA repair in STAG2-mutated cells.
- Combined treatment with PARP inhibitors and DNA-damaging agents showed enhanced efficacy in STAG2-mutated cells.
Conclusions:
- PARP is a potential therapeutic target for tumors with inactivating STAG2 mutations.
- Determining STAG2 mutation status is recommended for patient stratification in clinical trials involving PARP inhibitors.
- This study supports the prospective and retrospective correlation of STAG2 status with therapeutic response to PARP inhibitors.
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