Understanding mechanistic role of SAMHD1 in DNA damage response and therapeutic benefit for malignant glioma

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Project Summary/Abstract Malignant Glioma is the most commonly diagnosed adult central nervous system malignancy, and carries a poor prognosis. The conventional treatment for malignant glioma is surgical resection followed by radiation therapy (RT) and the chemotherapeutic drug, temozolomide (TMZ). Despite attempts to improve the probability of survival in patients with this combination of therapies, there has been only modest success. Thus, there is urgent need to develop a better therapy to improve patient outcomes. TMZ and RT cause cancer cell death by inducing DNA damage; however, if DNA repair pathways are intact and effective, there is a high probability that a cell may develop resistance to these treatments. Thus, understanding the underlying cause of treatment resistance could lead to the development of more effective therapies and, ultimately, improve patients' prognosis. Therefore, identifying novel genes that can be targeted to alleviate treatment resistance in malignant glioma will contribute significantly to ongoing research efforts. We identified a novel role for sterile alpha motif and HD domain containing-protein 1 (SAMHD1) in promoting DNA end resection to facilitate DNA double-strand break (DSB) repair by homologous recombination (HR). SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase with a well-defined role in restricting HIV-1 infection in nondividing cells by depleting dNTPs required for reverse transcription. Our preliminary data indicate that SAMHD1 depletion in cancer cells causes hypersensitivity to DNA DSB-inducing agents. We have also shown that SAMHD1 is recruited to DNA DSBs in response to DNA damage. SAMHD1 interacts with CtIP following DNA damage and recruits CtIP to DNA DSBs to facilitate DNA end resection and HR independent of its dNTPase activity. SAMHD1 is targeted for proteasomal degradation by the viral accessory protein, Vpx. We have data showing that various cancer cell lines treated with Vpx have diminished levels of SAMHD1 compared to endogenous levels, and subsequently, have increased sensitivity to DNA damage inducing therapeutic agents. Strikingly, malignant glioma patients with low SAMHD1 levels show a significantly higher probability of overall survival. Furthermore, oligodendroglioma, astrocytoma and glioblastoma tumor samples show significantly higher expression of SAMHD1 as compared to normal brain tissue. Interestingly, GBM, the most aggressive form of glioma, expresses the highest level of SAMHD1. Taken together, our preliminary findings suggest that SAMHD1 could be a potential therapeutic target for malignant glioma treatment. As such, the overall objective of my proposal is to determine the mechanisms by which SAMHD1 directs DNA DSB repair to mediate treatment resistance in malignant glioma and to see how we can utilize this knowledge to improve glioma treatment.