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Abstract: Tumor suppressor p53 is a well-characterized transcription factor that binds DNA. More enigmatic are the RNA-binding properties of p53 and their physiological relevance. We used three sensitive co-immunoprecipitation methods in an attempt to detect RNAs that tightly associate with p53 in cultured human cells. Although recombinant p53 protein binds RNA in a sequence-nonspecific mode, we do not detect specific in vivo RNA binding by p53. These results suggest that RNA binding is prevented by post-translational p53 modifications. A ribonucleoprotein (not p53) is purified by multiple IgG monoclonal antibodies (including anti-p53 antibodies) from both p53 +/+ and p53 null cells. Caution is therefore required in interpreting RNA co-immunoprecipitation experiments. Though not formally excluded, these results do not support models in which p53 binds specific RNA partners in vivo. [Copyright &y& Elsevier]