ku-55933 and benzyloxycarbonylleucyl-leucyl-leucine-aldehyde

In response to DNA damage, mammalian cells trigger the p53-dependent transcriptional induction of factors that regulate DNA repair, cell-cycle progression, or cell survival. Through differential proteomics, we identify heterogeneous nuclear ribonucleoprotein K (hnRNP K) as being rapidly induced by DNA damage in a manner that requires the DNA-damage signaling kinases ATM or ATR. Induction of hnRNP K ensues through the inhibition of its ubiquitin-dependent proteasomal degradation mediated by the ubiquitin E3 ligase HDM2/MDM2. Strikingly, hnRNP K depletion abrogates transcriptional induction of p53 target genes and causes defects in DNA-damage-induced cell-cycle-checkpoint arrests. Furthermore, in response to DNA damage, p53 and hnRNP K are recruited to the promoters of p53-responsive genes in a mutually dependent manner. These findings establish hnRNP K as a new HDM2 target and show that, by serving as a cofactor for p53, hnRNP K plays key roles in coordinating transcriptional responses to DNA damage.

Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Cell Cycle; Cell Cycle Proteins; Cell Line; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Cysteine Proteinase Inhibitors; DNA Damage; DNA-Binding Proteins; Gene Expression; Heterogeneous-Nuclear Ribonucleoprotein K; Humans; Leupeptins; Morpholines; Phleomycins; Promoter Regions, Genetic; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-mdm2; Pyrones; Radiation, Ionizing; Ribonucleoproteins; RNA, Small Interfering; Transcription, Genetic; Transfection; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Ubiquitin; Ultraviolet Rays