Abstract B26: Ape1/Ref-1 directs DNA repair pathway choice, linked to Chk2 signaling, critical for glioblastoma response to chemotherapy
Authors: Stroebel Thomas , Madlener Sibylle , Tuna Serkan , Vose Sarah , Morse Daniella , Tannous Bakhos A. , Lagerweij Tonny , Wurdinger Thomas , Marosi Christine , Slavc Irene , Vierlinger Klemens , Saydam Okay , Price Brendan D. , Demple Bruce , Saydam Nurten 
Published: May 2015

The predominant human apurinic/apyrimidinic (AP) endonuclease 1, Ape1 (also known as Ref-1) plays a central role in the pathways of base excision repair (BER) of DNA. BER is the major system for correcting the oxidative DNA damage that arises endogenously as a result of metabolism. Spontaneous hydrolytic decay of DNA or DNA glycosylase-mediated hydrolysis of N-glycosyl bonds generates AP sites at an estimated frequency of &gt;10,000 per day in each human cell. If unrepaired, non-instructional AP sites potently block DNA replication and thereby cause toxicity. Thus, the proper repair of AP sites is crucial for maintaining genome stability. Genetic studies in mice support the essential role of Ape1 in cellular viability. In this study, we have explored the molecular details of Ape1-mediated genome maintenance mechanisms, and applied glioblastoma multiforme (GBM) tumor model for investigation of the functional significance of the Ape1-mediated cell responses to chemotherapy. Here we present evidence that Ape1 links to a Chk2-associated tumor suppressor pathway, and is necessary for proper execution of DNA damage-induced checkpoints. Furthermore, our study revealed an unexpected role for Ape1 in BRCA1-mediated homologous recombination (HR) repair of DNA breaks, which is crucial for directing DNA repair pathway choices. The analyses of the TCGA data set for GBM showed that Ape1 and Chk2 are coordinately regulated in glioblastoma multiforme, and increased expression of APEX1 gene coding for Ape1 positively correlates with better survival of glioblastoma patients. GBM is the most common and deadly type of primary brain tumor. The current therapy remains relatively ineffective due to diffuse infiltration and intrinsic resistance of GBM cells. Thus, there is an urgent need for rational treatment protocols for the GBM cure. Our study provides evidence for critical importance of the survival network of Ape1 and Chk2 in GBM response to chemotherapy. Regulation of the equilibrium between Ape1 and Chk2 enables tumor cells switch between DNA repair pathways to favor cell survival. Identification of tumor-specific pre-dominant DNA repair pathways and interruption of such survival networks can be a useful strategy for designing novel therapies for GBM.

Citation Format: Thomas Stroebel, Sibylle Madlener, Serkan Tuna, Sarah Vose, Daniella Morse, Bakhos A. Tannous, Tonny Lagerweij, Thomas Wurdinger, Christine Marosi, Irene Slavc, Klemens Vierlinger, Okay Saydam, Brendan D. Price, Bruce Demple, Nurten Saydam. Ape1/Ref-1 directs DNA repair pathway choice, linked to Chk2 signaling, critical for glioblastoma response to chemotherapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B26.