Requirement for theXrcc1DNA Base Excision Repair Gene during Early Mouse Development

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.

A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer

“…Sp1 is generally considered as a transcriptional activator; however, as demonstrated in many previous studies, Sp1 may also function as a transcriptional inhibitor, repressing gene transcription in certain promoter contexts (Pagliuca et al, 1998;Shou et al, 1998;Dean et al, 2000;Li and Ou, 2001;Won et al, 2002). As XRCC1 plays important roles in BER (Thompson et al, 1990;Tebbs et al, 1999;Weinfeld et al, 2001;Caldecott, 2003), reduced expression of the protein would be expected to impair BER ability and hence increase the risk of lung cancer.…”

“…As a scaffold protein in BER, the X-ray repair cross-complementing 1 (XRCC1) assembles a DNAprotein complex at the damage site with poly(ADPribose) polymerase, DNA polymerase-b and DNA ligase IIIa to complete the repair process (Weinfeld et al, 2001;Caldecott, 2003). The importance of XRCC1 in maintaining genomic stability is indicated by an increased frequency of spontaneous chromosome aberrations and deletions in XRCC1 mutant cells and by embryonic lethality in XRCC1 knockout mice (Thompson et al, 1990;Tebbs et al, 1999).…”

Mouse models of XRCC1 DNA repair polymorphisms and cancer

“…XRCC1 null mouse line XRCC1 gene knockout in mice results in embryonic lethality, demonstrating it is essential for development (Tebbs et al, 1999). However, it is problematic to study any adult phenotype that may be the result of XRCC1 deletion.…”

“…Cells lacking the gene product are hypersensitive to ionizing radiation, hydrogen peroxide, camptothecin and alkylating agents (reviewed by Caldecott, 2003). In addition, mutant cells show elevated frequency of spontaneous chromosomal aberrations and deletions, and null mutant mice exhibit an embryonic lethal phenotype indicating the importance of XRCC1 for genetic stability (Tebbs et al, 1999). A recent study has shown that XRCC1 is required for efficient DNA SSB repair (Brem and Hall, 2005).…”

ATP for the DNA Ligation Step in Base Excision Repair Is Generated from Poly(ADP-ribose)

“…X-ray repair cross-complementing protein-1 (XRCC1) was the first human gene product isolated that mediates the cellular response to ionizing radiation (15). This protein is apparently essential and required for the BER pathway (16). Recent investigations demonstrated specific interactions of XRCC1 with Pol ␤, DNA ligase III (Lig III), and PARP-1 (13,(17)(18)(19)(20).…”