Radiation-induced transgenerational alterations in genome stability and DNA damage
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Radiation-induced transgenerational alterations in genome stability and DNA damage. / Barber, R C; Hickenbotham, P; Hatch, T; Kelly, D; Topchiy, N; Almeida, G M; Jones, G D D; Johnson, G E; Parry, J M; Rothkamm, K; Dubrova, Y E.
In: ONCOGENE, Vol. 25, No. 56, 30.11.2006, p. 7336-42.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Radiation-induced transgenerational alterations in genome stability and DNA damage
AU - Barber, R C
AU - Hickenbotham, P
AU - Hatch, T
AU - Kelly, D
AU - Topchiy, N
AU - Almeida, G M
AU - Jones, G D D
AU - Johnson, G E
AU - Parry, J M
AU - Rothkamm, K
AU - Dubrova, Y E
PY - 2006/11/30
Y1 - 2006/11/30
N2 - Mutation induction in directly exposed cells is currently regarded as the main component of the genetic risk of ionizing radiation for humans. However, recent data on the transgenerational increases in mutation rates in the offspring of irradiated parents indicate that the genetic risk could be greater than predicted previously. Here, we have analysed transgenerational changes in mutation rates and DNA damage in the germline and somatic tissues of non-exposed first-generation offspring of irradiated inbred male CBA/Ca and BALB/c mice. Mutation rates at an expanded simple tandem repeat DNA locus and a protein-coding gene (hprt) were significantly elevated in both the germline (sperm) and somatic tissues of all the offspring of irradiated males. The transgenerational changes in mutation rates were attributed to the presence of a persistent subset of endogenous DNA lesions (double- and single-strand breaks), measured by the phosphorylated form of histone H2AX (gamma-H2AX) and alkaline Comet assays. Such remarkable transgenerational destabilization of the F(1) genome may have important implications for cancer aetiology and genetic risk estimates. Our data also provide important clues on the still unknown mechanisms of radiation-induced genomic instability.
AB - Mutation induction in directly exposed cells is currently regarded as the main component of the genetic risk of ionizing radiation for humans. However, recent data on the transgenerational increases in mutation rates in the offspring of irradiated parents indicate that the genetic risk could be greater than predicted previously. Here, we have analysed transgenerational changes in mutation rates and DNA damage in the germline and somatic tissues of non-exposed first-generation offspring of irradiated inbred male CBA/Ca and BALB/c mice. Mutation rates at an expanded simple tandem repeat DNA locus and a protein-coding gene (hprt) were significantly elevated in both the germline (sperm) and somatic tissues of all the offspring of irradiated males. The transgenerational changes in mutation rates were attributed to the presence of a persistent subset of endogenous DNA lesions (double- and single-strand breaks), measured by the phosphorylated form of histone H2AX (gamma-H2AX) and alkaline Comet assays. Such remarkable transgenerational destabilization of the F(1) genome may have important implications for cancer aetiology and genetic risk estimates. Our data also provide important clues on the still unknown mechanisms of radiation-induced genomic instability.
KW - Animals
KW - Base Sequence
KW - Comet Assay
KW - DNA/radiation effects
KW - DNA Damage
KW - DNA Primers
KW - DNA Repair
KW - Genomic Instability
KW - Hypoxanthine Phosphoribosyltransferase/genetics
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred CBA
KW - Mutation
KW - Tandem Repeat Sequences
U2 - 10.1038/sj.onc.1209723
DO - 10.1038/sj.onc.1209723
M3 - SCORING: Journal article
C2 - 16751800
VL - 25
SP - 7336
EP - 7342
JO - ONCOGENE
JF - ONCOGENE
SN - 0950-9232
IS - 56
ER -