The DNA repair function of CUX1 contributes to radioresistance.
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.
Goodman Cancer Research Centre, McGill University, Montreal, Quebec, H3A 1A3, Canada.
Zubaidah M
ZM
Ramdzan
Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08903, USA.
Vasudeva
V
Ginjala
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
Jordan B
JB
Pinder
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
Dudley
D
Chung
Goodman Cancer Research Centre, McGill University, Montreal, Quebec, H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, H3A 1A3, Canada.
Caroline M
CM
Donovan
Goodman Cancer Research Centre, McGill University, Montreal, Quebec, H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, H3A 1A3, Canada.
Simran
S
Kaur
Goodman Cancer Research Centre, McGill University, Montreal, Quebec, H3A 1A3, Canada.
Lam
L
Leduy
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
Graham
G
Dellaire
Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08903, USA.
Shridar
S
Ganesan
Goodman Cancer Research Centre, McGill University, Montreal, Quebec, H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, H3A 1A3, Canada.|Department of Medicine, McGill University, Montreal, Quebec, H3A 1A3, Canada.|Department of Oncology, McGill University, Montreal, Quebec, H3A 1A3, Canada.
Alain
A
Nepveu
D045744:Cell Line, Tumor; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D018613:Microscopy, Confocal; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011836:Radiation Tolerance / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
C080632:CUX1 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D014157:Transcription Factors; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human
CUX1; OGG1; base excision repair; radioresistance