Requirement for the Xrcc1 DNA base excision repair gene during early mouse development.
Surveillance and repair of DNA damage are essential for maintaining the integrity of the genetic information that is needed for normal development. Several multienzyme pathways, including the excision repair of damaged or missing bases, carry out DNA repair in mammals. We determined the developmental role of the X-ray cross-complementing (Xrcc)-1 gene, which is central to base excision repair, by generating a targeted mutation in mice. Heterozygous matings produced Xrcc1-/- embryos at early developmental stages, but not Xrcc1-/- late-stage fetuses or pups. Histology showed that mutant (Xrcc1-/-) embryos arrested at embryonic day (E) 6.5 and by E7.5 were morphologically abnormal. The most severe abnormalities observed in mutant embryos were in embryonic tissues, which showed increased cell death in the epiblast and an altered morphology in the visceral embryonic endoderm. Extraembryonic tissues appeared relatively normal at E6.5-7.5. Even without exposure to DNA-damaging agents, mutant embryos showed increased levels of unrepaired DNA strand breaks in the egg cylinder compared with normal embryos. Xrcc1-/- cell lines derived from mutant embryos were hypersensitive to mutagen-induced DNA damage. Xrcc1 mutant embryos that were also made homozygous for a null mutation in Trp53 underwent developmental arrest after only slightly further development, thus revealing a Trp53-independent mechanism of embryo lethality. These results show that an intact base excision repair pathway is essential for normal early postimplantation mouse development and implicate an endogenous source of DNA damage in the lethal phenotype of embryos lacking this repair capacity.
Tebbs
R S
RS
Department of Dermatology, University of California at San Francisco, San Francisco, California, 94143, USA.
Flannery
M L
ML
Meneses
J J
JJ
Hartmann
A
A
Tucker
J D
JD
Thompson
L H
LH
Cleaver
J E
JE
Pedersen
R A
RA
D000818:Animals; D016923:Cell Death; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D004622:Embryo, Mammalian / Q000002:abnormalities; D047108:Embryonic Development; D005260:Female; D018390:Gene Targeting; D020043:Genes, Essential; D051379:Mice; D008817:Mice, Mutant Strains / Q000196:embryology*; D008938:Mitosis; D011247:Pregnancy; D012854:Sister Chromatid Exchange; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1
D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D000076105:X-ray Repair Cross Complementing Protein 1; C000619352:Xrcc1 protein, mouse