Requirement for the Xrcc1 DNA base excision repair gene during early mouse development

Robert S. Tebbs, Margaret L. Flannery, Juanito J. Meneses, Andreas Hartmann, James D. Tucker, Larry H. Thompson, James E. Cleaver, Roger A. Pedersen

Research output: Contribution to journalArticle

273 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)513-529
Number of pages17
JournalDevelopmental Biology
Volume208
Issue number2
DOIs
StatePublished - Apr 15 1999
Externally publishedYes

Keywords

  • Base excision repair
  • DNA damage
  • Embryonic lethality
  • Gene targeting
  • Mouse
  • XRCC1

ASJC Scopus subject areas

  • Developmental Biology

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  • Cite this

    Tebbs, R. S., Flannery, M. L., Meneses, J. J., Hartmann, A., Tucker, J. D., Thompson, L. H., Cleaver, J. E., & Pedersen, R. A. (1999). Requirement for the Xrcc1 DNA base excision repair gene during early mouse development. Developmental Biology, 208(2), 513-529. https://doi.org/10.1006/dbio.1999.9232