TY - JOUR
T1 - Accumulation of the common mitochondrial DNA deletion induced by ionizing radiation
AU - Prithivirajsingh, Sheela
AU - Story, Michael D.
AU - Bergh, Sherry A.
AU - Geara, Fady B.
AU - Kian Ang, K.
AU - Ismail, Sheikh M.
AU - Stevens, Craig W.
AU - Buchholz, Thomas A.
AU - Brock, William A.
N1 - Funding Information:
This study was supported by NIH grant (CA06294) and Cancer Research program of the M.D. Anderson Cancer Center.
PY - 2004/7/30
Y1 - 2004/7/30
N2 - Point mutations and deletions in mitochondrial DNA (mtDNA) accumulate as a result of oxidative stress, including ionizing radiation. As a result, dysfunctional mitochondria suffer from a decline in oxidative phosphorylation and increased release of superoxides and other reactive oxygen species (ROS). Through this mechanism, mitochondria have been implicated in a host of degenerative diseases. Associated with this type of damage, and serving as a marker of total mtDNA mutations and deletions, the accumulation of a specific 4977-bp deletion, known as the common deletion (Δ-mtDNA4977), takes place. The Δ-mtDNA4977 has been reported to increase with age and during the progression of mitochondrial degeneration. The purpose of this study was to investigate whether ionizing radiation induces the formation of the common deletion in a variety of human cell lines and to determine if it is associated with cellular radiosensitivity. Cell lines used included eight normal human skin fibroblast lines, a radiosensitive non-transformed and an SV40 transformed ataxia telangiectasia (AT) homozygous fibroblast line, a Kearns Sayre Syndrome (KSS) line known to contain mitochondrial deletions, and five human tumor lines. The Δ-mtDNA4977 was assessed by polymerase chain reaction (PCR). Significant levels of Δ-mtDNA4977 accumulated 72 h after irradiation doses of 2, 5, 10 or 20 Gy in all of the normal lines with lower response in tumor cell lines, but the absolute amounts of the induced deletion were variable. There was no consistent dose-response relationship. SV40 transformed and non-transformed AT cell lines both showed significant induction of the deletion. However, the five tumor cell lines showed only a modest induction of the deletion, including the one line that was deficient in DNA damage repair. No relationship was found between sensitivity to radiation-induced deletions and sensitivity to cell killing by radiation.
AB - Point mutations and deletions in mitochondrial DNA (mtDNA) accumulate as a result of oxidative stress, including ionizing radiation. As a result, dysfunctional mitochondria suffer from a decline in oxidative phosphorylation and increased release of superoxides and other reactive oxygen species (ROS). Through this mechanism, mitochondria have been implicated in a host of degenerative diseases. Associated with this type of damage, and serving as a marker of total mtDNA mutations and deletions, the accumulation of a specific 4977-bp deletion, known as the common deletion (Δ-mtDNA4977), takes place. The Δ-mtDNA4977 has been reported to increase with age and during the progression of mitochondrial degeneration. The purpose of this study was to investigate whether ionizing radiation induces the formation of the common deletion in a variety of human cell lines and to determine if it is associated with cellular radiosensitivity. Cell lines used included eight normal human skin fibroblast lines, a radiosensitive non-transformed and an SV40 transformed ataxia telangiectasia (AT) homozygous fibroblast line, a Kearns Sayre Syndrome (KSS) line known to contain mitochondrial deletions, and five human tumor lines. The Δ-mtDNA4977 was assessed by polymerase chain reaction (PCR). Significant levels of Δ-mtDNA4977 accumulated 72 h after irradiation doses of 2, 5, 10 or 20 Gy in all of the normal lines with lower response in tumor cell lines, but the absolute amounts of the induced deletion were variable. There was no consistent dose-response relationship. SV40 transformed and non-transformed AT cell lines both showed significant induction of the deletion. However, the five tumor cell lines showed only a modest induction of the deletion, including the one line that was deficient in DNA damage repair. No relationship was found between sensitivity to radiation-induced deletions and sensitivity to cell killing by radiation.
KW - AT, ataxia telangiectasia
KW - IR, ionizing radiation
KW - Ionizing radiation
KW - KSS, Kearns Sayre Syndrome
KW - Mutation and common deletion
KW - PCR
KW - PCR, polymerase chain reaction
KW - ROS, reactive oxygen species
KW - SF, survival fraction
KW - mtDNA
KW - mtDNA, mitochondrial DNA
UR - http://www.scopus.com/inward/record.url?scp=3342950130&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3342950130&partnerID=8YFLogxK
U2 - 10.1016/j.febslet.2004.06.078
DO - 10.1016/j.febslet.2004.06.078
M3 - Article
C2 - 15280047
AN - SCOPUS:3342950130
SN - 0014-5793
VL - 571
SP - 227
EP - 232
JO - FEBS Letters
JF - FEBS Letters
IS - 1-3
ER -