Telomere shortening is associated with malformation in p53-deficient mice after irradiation during specific stages of development.
The natural ends of linear chromosomes, the telomeres, recruit specific proteins in the formation of protective caps that preserve the integrity of the genome. Unprotected chromosomes induce DNA damage checkpoint cascades and ultimately lead to senescence both in mouse and man in a p53 dependent manner and initial telomere length setting therefore determines the proliferative capacity of each cell. Yet, only little information is available on telomere biology during embryonic development. We have previously shown that the p53 gene plays a crucial role in the development of malformations (exencephaly, gastroschisis, polydactyly, cleft palate and dwarfism) in control and irradiated mouse embryos. Here, we investigated telomere biology and the outcome of radiation exposure in wild type (p53+/+) and p53-mutant (p53+/-- and--/--) C57BL mouse foetuses irradiated at three different developmental stages. We show that telomeres are significantly shorter in malformed foetuses as compared to normal counterparts. In addition, our results indicate that the observed telomere attrition is primarily associated with p53-deficiency but is also modulated by irradiation, more specifically during the gastrulation and organogenesis stages. In conclusion, we formulate a hypothesis in which telomere shortening is linked to the absence of p53 in mouse foetuses and that when, in the presence of shorter telomeres, these foetuses are irradiated, the chance for the occurrence of developmental defects increases substantially.
Bekaert
Sofie
S
Laboratory for Biochemistry and Molecular Cytology, Department for Molecular Biotechnology, Faculty of Bioscience Engineering FBE, Ghent University, Belgium.
Derradji
Hanane
H
De Meyer
Tim
T
Michaux
Arlette
A
Buset
Jasmine
J
Neefs
Mieke
M
Mergeay
Max
M
Jacquet
Paul
P
Van Oostveldt
Patrick
P
Baatout
Sarah
S
D000016:Abnormalities, Radiation-Induced; D000818:Animals; D043171:Chromosomal Instability / Q000528:radiation effects*; D004249:DNA Damage; D047108:Embryonic Development / Q000235:genetics / Q000528:radiation effects*; D005260:Female; D016158:Genes, p53; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D018345:Mice, Knockout; D011247:Pregnancy; D016615:Telomere / Q000235:genetics / Q000528:radiation effects*; D034501:Telomere-Binding Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000378:metabolism
D034501:Telomere-Binding Proteins; D016159:Tumor Suppressor Protein p53