Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice.
Repair of DNA damage by homologous recombination has only recently been established as an important mechanism in maintaining genetic stability in mammalian cells. The recently cloned Xrcc2 gene is a member of the mammalian Rad51 gene family, thought to be central to homologous recombination repair. To understand its function in mammals, we have disrupted Xrcc2 in mice. No Xrcc2(-/-) animals were found alive, with embryonic lethality occurring from mid-gestation. Xrcc2(-/-) embryos surviving until later stages of embryogenesis commonly showed developmental abnormalities and died at birth. Neonatal lethality, apparently due to respiratory failure, was associated with a high frequency of apoptotic death of post- mitotic neurons in the developing brain, leading to abnormal cortical structure. Embryonic cells showed genetic instability, revealed by a high level of chromosomal aberrations, and were sensitive to gamma-rays. Our findings demonstrate that homologous recombination has an important role in endogenous damage repair in the developing embryo. Xrcc2 disruption identifies a range of defects that arise from malfunction of this repair pathway, and establishes a previously unidentified role for homologous recombination repair in correct neuronal development.
Deans
B
B
Medical Research Council, Radiation and Genome Stability Unit and Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
Griffin
C S
CS
Maconochie
M
M
Thacker
J
J
D000818:Animals; D017209:Apoptosis; D001755:Blastocyst / Q000166:cytology* / Q000502:physiology; D002678:Chimera; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005314:Embryonic and Fetal Development / Q000235:genetics*; D005313:Fetal Death; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D009420:Nervous System / Q000196:embryology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D016133:Polymerase Chain Reaction; D013234:Stem Cells
D004268:DNA-Binding Proteins; C491866:Xrcc2 protein, mouse