MYC can induce DNA breaks in vivo and in vitro independent of reactive oxygen species.
MYC overexpression is thought to initiate tumorigenesis by inducing cellular proliferation and growth and to be restrained from causing tumorigenesis by inducing cell cycle arrest, cellular senescence, and/or apoptosis. Here we show that MYC can induce DNA breaks both in vitro and in vivo independent of increased production of reactive oxygen species (ROS). We provide an insight into the specific circumstances under which MYC generates ROS in vitro and propose a possible mechanism. We found that MYC induces DNA double-strand breaks (DSBs) independent of ROS production in murine lymphocytes in vivo as well as in normal human foreskin fibroblasts (NHFs) in vitro in normal (10%) serum, as measured by gammaH2AX staining. However, NHFs cultured in vitro in low serum (0.05%) and/or ambient oxygen saturation resulted in ROS-associated oxidative damage and DNA single-strand breaks (SSBs), as measured by Ape-1 staining. In NHFs cultured in low versus normal serum, MYC induced increased expression of CYP2C9, a gene product well known to be associated with ROS production. Specific inhibition of CYP2C9 by small interfering RNA was shown to partially inhibit MYC-induced ROS production. Hence, MYC overexpression can induce ROS and SSBs under some conditions, but generally induces widespread DSBs in vivo and in vitro independent of ROS production.
Ray
Suma
S
Division of Oncology, Department of Medicine and Pathology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305, USA.
Atkuri
Kondala R
KR
Deb-Basu
Debabrita
D
Adler
Adam S
AS
Chang
Howard Y
HY
Herzenberg
Leonore A
LA
Felsher
Dean W
DW
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D004249:DNA Damage / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology
D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases