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J Radiat Res
2024 Apr 20; doi: 10.1093/jrr/rrae012.
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Changes in repair pathways of radiation-induced DNA double-strand breaks at the midblastula transition in Xenopus embryo.
Morozumi R
,
Shimizu N
,
Tamura K
,
Nakamura M
,
Suzuki A
,
Ishiniwa H
,
Ide H
,
Tsuda M
.
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Ionizing radiation (IR) causes DNA damage, particularly DNA double-strand breaks (DSBs), which have significant implications for genome stability. The major pathways of repairing DSBs are homologous recombination (HR) and nonhomologous end joining (NHEJ). However, the repair mechanism of IR-induced DSBs in embryos is not well understood, despite extensive research in somatic cells. The externally developing aquatic organism, Xenopus tropicalis, serves as a valuable model for studying embryo development. A significant increase in zygotic transcription occurs at the midblastula transition (MBT), resulting in a longer cell cycle and asynchronous cell divisions. This study examines the impact of X-ray irradiation on Xenopus embryos before and after the MBT. The findings reveal a heightened X-ray sensitivity in embryos prior to the MBT, indicating a distinct shift in the DNA repair pathway during embryo development. Importantly, we show a transition in the dominant DSB repair pathway from NHEJ to HR before and after the MBT. These results suggest that the MBT plays a crucial role in altering DSB repair mechanisms, thereby influencing the IR sensitivity of developing embryos.
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38648785
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Institute of Environmental Radioactivity, Fukushima University, 19KK0210 JSPS KAKENHI, 2020-22 KOSE Cosmetology Research Foundation, Takahashi Industrial and Economic Research Foundation, Hoansha Foundation, Program of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science
Fig. 1Effects of X-ray irradiation on the early development of X. tropicalis embryos. (A) Timeline of the experimental design: embryos were irradiated either before the MBT at 32 cell stage (4 hpf) or after the MBT at the late blastula stage (7 hpf). Survival and malformation were analyzed at the late tail bud stage (48 hpf). (B) Representative images: malformations observed at the late tail bud stage (48 hpf). (C) Survival and malformation rates: left: survival rates; right: malformation rates of X. tropicalis embryos irradiated with indicated doses of X-rays before the MBT (squares) and after the MBT (circles). The values are presented as mean and standard deviation from three independent irradiation experiments (50 embryos per replicate).
Fig. 2Effects of DNA DSB repair inhibitors on the survival and malformation of embryos irradiated before the MBT. (A) Time-courses of DNA-PKcs and RAD51 expression: time-courses of the expression levels of DNA-PKcs (left) and RAD51 (right) as revealed by polyA + RNA (RNA-seq) during early Xenopus development. Data sourced from Owens et al. [19]. (B) Experimental design timeline: embryos were irradiated before the MBT at 4 hpf, 1 h after the addition of inhibitors (NU7026 or RI-1) and incubated with inhibitors from 3 to 48 hpf. (C) NU7026 Treatment: left: survival rates; right: malformation rates of embryos treated with NU7026 (a DNA-PKcs inhibitor, open circles) or NU7026 + X-rays (1 Gy, closed circles). (D) RI-1 treatment: left: survival rates; right: malformation rates of embryos treated with RI-1 (a RAD51 inhibitor, open circles) or RI-1 + X-rays (1 Gy, closed circles).
Fig. 3Effects of DSB repair inhibitors on the survival and malformation of embryos irradiated after the MBT. (A) Experimental design timeline: embryos were irradiated after the MBT at 7 hpf, 1 h after the addition of inhibitors (NU7026 or RI-1), and incubated with inhibitors from 6 to 48 hpf. (B) NU7026 treatment: left: survival rates; right: malformation rates of embryos treated with NU7026 (a DNA-PKcs inhibitor, open circles) or NU7026 + X-rays (1 Gy, closed circles). (C) RI-1 treatment: left: survival rates; right: malformation rates of embryos treated with RI-1 (a RAD51 inhibitor, open circles) or RI-1 + X-rays (1 Gy, closed circles).
Fig. 4Model of changes in DSB repair pathways in developing Xenopus embryo. In developing Xenopus embryos, the major contributor to the repair of IR-induced DSBs is NHEJ before the MBT, whereas it changes from NHEJ to HR after the MBT.
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