title: XRCC3 depletion induces spontaneous DNA breaks and p53-dependent cell death.
abstract: In vertebrate cells, Xrcc3 initiates the repair of exogenous induced-DNA breaks during S and G(2)/M phases of the cell cycle by homologous recombination. However, much less is known of the role of Xrcc3 in the response to spontaneous DNA breaks. Using a siRNA approach, we show that depletion of XRCC3 inhibits the proliferation of MCF7 breast cancer cells. This inhibition of replication coincides with the accumulation of DNA breaks, as shown by the comet assay. Cell cycle specific analysis of gammaH2AX expression shows that S and G2/M phase cells express the highest fraction of gammaH2AX positive cells. This is consistent with replication-dependent accumulation of DNA breaks and deficient homologous recombination. While the induction of gammaH2AX is followed by cell death in parental cells, a p53 knockdown derivative becomes more resistant to XRCC3 depletion-induced death without changes in the levels of gammaH2AX. These results show that XRCC3 is required for the proliferation of MCF7 cells, and that decrease in its expression leads to the accumulation of DNA breaks and the induction of p53-dependent cell death.
authors.affiliation: Oncology Department, MCETC, and Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Loignon
authors.forename: Lilian
authors.initials: L
authors.lastname: Amrein
authors.forename: Michael
authors.initials: M
authors.lastname: Dunn
authors.forename: Raquel
authors.initials: R
authors.lastname: Aloyz
mesh_terms: D016923:Cell Death / Q000235:genetics; D053960:DNA Breaks; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C110901:X-ray repair cross complementing protein 3