Retracted: hnRNP K: an HDM2 target and transcriptional coactivator of p53 in response to DNA damage.
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.
Moumen
Abdeladim
A
The Wellcome Trust and Cancer Research UK Gurdon Institute and Department of Zoology, Cambridge University, Tennis Court Road, Cambridge CB2 1QN, United Kingdom.
Masterson
Philip
P
O'Connor
Mark J
MJ
Jackson
Stephen P
SP
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D010692:Phleomycins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays
C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D007976:Leupeptins; D009025:Morpholines; D010692:Phleomycins; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D011753:Pyrones; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C072074:HNRNPK protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde