Hence, our study as presented here not only delineates the detailed mechanism by which RPL22/eL22 suppresses cancer cell survival by blocking the MDM2-p53 feedback loop and consequently activating p53 probably as part of the ribosome-free ribosomal protein sub-complex, but also provides a new molecular insight into understanding clinical relevance of high mutation rate of RPL22/eL22 in some human cancers. This evidence concerns the gene TP53 and cancer.