The DNA repair function of CUX1 contributes to radioresistance
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Zubaidah M. Ramdzan1, Vasudeva Ginjala3,*, Jordan B. Pinder4,*, Dudley Chung4,*, Caroline M. Donovan1,2,*, Simran Kaur1,2, Lam Leduy1, Graham Dellaire4, Shridar Ganesan3, Alain Nepveu1,2,3,4
1Goodman Cancer Research Centre, McGill University, Montreal, Quebec, H3A 1A3, Canada
2Department of Biochemistry, McGill University, Montreal, Quebec, H3A 1A3, Canada
3Department of Medicine, McGill University, Montreal, Quebec, H3A 1A3, Canada
4Department of Oncology, McGill University, Montreal, Quebec, H3A 1A3, Canada
*These authors contributed equally to this work
Alain Nepveu, email: [email protected]
Keywords: CUX1, OGG1, base excision repair, radioresistance
Received: March 30, 2016 Accepted: January 19, 2017 Published: January 28, 2017
Ionizing radiation generates a broad spectrum of oxidative DNA lesions, including oxidized base products, abasic sites, single-strand breaks and double-strand breaks. The CUX1 protein was recently shown to function as an auxiliary factor that stimulates enzymatic activities of OGG1 through its CUT domains. In the present study, we investigated the requirement for CUX1 and OGG1 in the resistance to radiation. Cancer cell survival following ionizing radiation is reduced by CUX1 knockdown and increased by higher CUX1 expression. However, CUX1 knockdown is sufficient by itself to reduce viability in many cancer cell lines that exhibit high levels of reactive oxygen species (ROS). Consequently, clonogenic results expressed relative to that of non-irradiated cells indicate that CUX1 knockdown confers no or modest radiosensitivity to cancer cells with high ROS. A recombinant protein containing only two CUT domains is sufficient for rapid recruitment to DNA damage, acceleration of DNA repair and increased survival following radiation. In agreement with these findings, OGG1 knockdown and treatment of cells with OGG1 inhibitors sensitize cancer cells to radiation. Together, these results validate CUX1 and more specifically the CUT domains as therapeutic targets.
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