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Histone Ubiquitylation by Mdm2

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Science's STKE  23 Nov 2004:
Vol. 2004, Issue 260, pp. tw423
DOI: 10.1126/stke.2602004tw423

The Mdm2 oncoprotein is a critical inhibitor of the p53 tumor suppressor protein and apparently does so through multiple mechanisms. Mdm2 is an E3 ubiquitin ligase that ubiquitylates p53, thus targeting p53 for degradation by the proteasome. Mdm2 also directly binds the transactivation domain of p53 and interacts with the histone deactylase HDAC1 and with proteins of the basal transcription machinery. Minsky and Oren now add another mode of regulation. They show that Mdm2 interacts with histone H2B in vitro. In human embryonic kidney 293 cells, transfected FLAG-tagged H2B (expressed in amounts lower than those of endogenous H2B) immunoprecipitated with endogenous Mdm2. Mdm2 monoubiquitylated histones in vitro, and ubiquitylation of H2B was enhanced in cells transfected with Mdm2, tagged H2B, and tagged ubiquitin molecules. Deletion of the RING domain of Mdm2 (required for ubiquitin ligase activity) prevented the modification of H2B. To avoid complications in interpreting the effects on p53-induced transcription (due to the other modes of action of Mdm2), the authors used a transcription reporter system to show that Mdm2 also suppressed transcription in a manner that required the RING domain. Mdm2 was localized to the promoter of the p21 gene in human osteosarcoma cells. Together, the results indicate that, along with its other effects, Mdm2 may repress transcription through direct modification of histones by ubiquitylation.

N. Minsky, M. Oren, The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression. Mol. Cell 16, 631-639 (2004). [Online Journal]

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