Downregulation of PARP1 transcription by CDK4/6 inhibitors sensitizes human lung cancer cells to anticancer drug-induced death by impairing OGG1-dependent base excision repair
| العنوان: | Downregulation of PARP1 transcription by CDK4/6 inhibitors sensitizes human lung cancer cells to anticancer drug-induced death by impairing OGG1-dependent base excision repair |
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| المؤلفون: | Kinga Chmielewska, Żaneta Rygielska, Dominika Tempka, Paulina Tokarz, Magdalena Kluska, László Virág, Agnieszka Robaszkiewicz, Julita Pietrzak |
| المصدر: | Redox Biology Redox Biology, Vol 15, Iss C, Pp 316-326 (2018) |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cell cycle checkpoint, Lung Neoplasms, DNA Repair, Pyridines, Clinical Biochemistry, Poly (ADP-Ribose) Polymerase-1, Aminopyridines, BRCA1, breast cancer type 1 susceptibility protein, Biochemistry, Piperazines, DNA Glycosylases, PARP1, BRCA2, breast cancer type 2 susceptibility protein, SSBR, Single-strand break repair, Promoter Regions, Genetic, lcsh:QH301-705.5, BER, base excision repair, AP, apurinic/apyrimidinic site, Etoposide, lcsh:R5-920, iPARP1, inhibitor of PARP1, olaparib, Chemistry, Base excision repair, PD0332991, inhibitor of CDK4/6, palbociclib, Imbrance, CDK4/6, cyclin-dependent kinases 4 and 6, RAD51, RAD51 recombinase, HDAC1, histone deacetylase 1, Gene Expression Regulation, Neoplastic, EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit, DNA-PKcs/Ku, protein kinase, DNA-activated, catalytic polypeptide, iHDAC, inhibitor of histone deacetylases, 8-oxoguanine glycosylase (OGG1), lcsh:Medicine (General), DNAP β, DNA polymerase, beta, Research Paper, OGG1, 8-oxoguanine DNA glycosylase, NU6140, cyclin-dependent kinase 2 (CDK2) inhibitor, DNA damage, PCNA, proliferating cell nuclear antigen, FapyGua, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, PARP1, poly(ADP-ribose) polymerase 1, XRCC1, X-ray repair cross complementing 1, 03 medical and health sciences, pCMV3-PARP1, A549 cells transfected with vector carrying cDNA for PARP1, expressing higher level of PARP1 than pCMV3-EMPTY upon cell cycle arrest in G1, 8-oxo-Gua, 7,8-dihydro-8-oxoguanine, Cell Line, Tumor, Humans, iPRC2, inhibitor of EZH2, UNC1999, Cell growth, iOGG1, inhibitor of OGG1, O8, Poly(ADP-ribose) polymerase 1 (PARP1), Organic Chemistry, Daunorubicin, Oxo-8-G, 8-oxo-7,8-dihydroguanosine, pCMV3-EMPTY, A549 cells transfected with control vector, expressing basal level of PARP1, Cyclin-Dependent Kinase 4, Reactive oxygen species (ROS), DNA Repair Pathway, Cell Cycle Checkpoints, Hydrogen Peroxide, iCDK4/6, inhibitor of CDK4/6, MRE11, double strand break repair nuclease, SMARCA4, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4, 030104 developmental biology, lcsh:Biology (General), CDK2, cyclin-dependent kinase 2, LEE011, inhibitor of CDK4/6, ribociclib, Kisqali, DNA glycosylase, Purines, Cancer cell, Cancer research, NAC, N-acetyl-cysteine, HR, homologous recombination, Cyclin-dependent kinase 4 and 6 (iCDK4/6), DNA Damage |
| الوصف: | Hallmarks of cancer cells include uncontrolled growth and rapid proliferation; thus, cyclin-dependent kinases are a therapeutic target for cancer treatment. Treating non-small lung cancer cells with sublethal concentrations of the CDK4/6 inhibitors, ribociclib (LEE011) and palbociclib (PD0332991), which are approved by the FDA for anticancer therapies, caused cell cycle arrest in the G1 phase and suppression of poly(ADP-ribose) polymerase 1 (PARP1) transcription by inducing recruitment of the RB1-E2F1-HDAC1-EZH2 repressive complex to the PARP1 promoter. Downregulation of PARP1 made cancer cells vulnerable to death triggered by the anticancer drugs (WP631 and etoposide) and H2O2. All agents brought about redox imbalance and DNA strand breaks. The lack of PARP1 and poly(ADP-ribosyl)ation impaired the 8-oxoguanine glycosylase (OGG1)-dependent base excision DNA repair pathway, which is critical for maintaining the viability of cells treated with CDK4/6 inhibitors during oxidative stress. Upon G1 arrest of PARP1 overexpressing cells, OGG1 formed an immunoprecipitable complex with PARP1. Similar to cells with downregulated PARP1 expression, inhibition of PARP1 or OGG1 in PARP1 overexpressing cells resulted in DNA damage and decreased viability. Thus, PARP1 and OGG1 act in the same regulatory pathway, and PARP1 activity is required for OGG1-mediated repair of oxidative DNA damage in G1-arrested cells. In conclusion, the action of CDK4/6 inhibitors is not limited to the inhibition of cell growth. CDK4/6 inhibitors also lead to accumulation of DNA damage by repressing PARP1 in oxidatively stressed cells. Thus, CDK4/6 inhibitors sensitize G1-arrested cells to anticancer drugs, since these cells require PARP1-OGG1 functional interaction for cell survival. Graphical abstract fx1 Highlights • CDK4/6 inhibitors arrest cell proliferation in G1 phase. • iCDK4/6 sensitize cells to DNA damage-induced cell death by repressing PARP1. • PARP1 is required for OGG1 activity upon growth inhibition. • OGG1 repairs DNA damaged by WP631, etoposide, or H2O2 in G1-arrested cells. |
| تدمد: | 2213-2317 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::de6f77c1a1f3468245c3982273c155afTest https://pubmed.ncbi.nlm.nih.gov/29306194Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....de6f77c1a1f3468245c3982273c155af |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22132317 |
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