Association of p53 and MSH2 with recombinative repair complexes during S phase

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Abstract
Our previous recombination and biochemical analyses have led to the hypothesis that the tumor suppressor p53 monitors homologous recombination, a function which was previously attributed to the mismatch repair protein MSH2. Here, we show that a certain fraction of p53 is concentrated within discrete nuclear foci of cells synchronized in G1 phase, a pattern which becomes even more pronounced in S phase, especially after γ-ray treatment. p53 foci show some colocalization with MSH2 within distinct foci during G1 phase, while dots formed by BRCA1 display an independent localization pattern. In S phase nuclei, p53 foci almost completely colocalize with MSH2 foci and associate with the recombination surveillance factor BRCA1 in irradiated S phase cells. These p53 and MSH2 foci also show significant overlaps with foci of the recombination enzymes Rad50 and Rad51, which for the first time unveiled recombination-related functions of p53 in replicating cells. During S phase, p53 and MSH2 are maximally active in binding to early recombination intermediates, and coexist within the same nuclear DNA-protein complexes. Our data suggest that p53 is linked similarly to homologous recombination as MSH2 and provide further evidence for the new concept of a dual role of p53 in the regulation of growth and repair.