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000136739 0247_ $$2doi$$a10.1182/blood-2017-09-806679
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000136739 1001_ $$0P:(DE-He78)7f506158c27b5827cd9021cd3dad37c8$$aJethwa, Alexander$$b0$$eFirst author$$udkfz
000136739 245__ $$aTRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma.
000136739 260__ $$aStanford, Calif.$$bHighWire Press$$c2018
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000136739 520__ $$aTumors accumulate high levels of mutant p53 (mutp53), which contributes to mutp53 gain-of-function properties. The mechanisms that underlie such excessive accumulation are not fully understood. To discover regulators of mutp53 protein accumulation, we performed a large-scale RNA interference screen in a Burkitt lymphoma cell line model. We identified transformation/transcription domain-associated protein (TRRAP), a constituent of several histone acetyltransferase complexes, as a critical positive regulator of both mutp53 and wild-type p53 levels. TRRAP silencing attenuated p53 accumulation in lymphoma and colon cancer models, whereas TRRAP overexpression increased mutp53 levels, suggesting a role for TRRAP across cancer entities and p53 mutations. Through clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening, we identified a 109-amino-acid region in the N-terminal HEAT repeat region of TRRAP that was crucial for mutp53 stabilization and cell proliferation. Mass spectrometric analysis of the mutp53 interactome indicated that TRRAP silencing caused degradation of mutp53 via the MDM2-proteasome axis. This suggests that TRRAP is vital for maintaining mutp53 levels by shielding it against the natural p53 degradation machinery. To identify drugs that alleviated p53 accumulation similarly to TRRAP silencing, we performed a small-molecule drug screen and found that inhibition of histone deacetylases (HDACs), specifically HDAC1/2/3, decreased p53 levels to a comparable extent. In summary, here we identify TRRAP as a key regulator of p53 levels and link acetylation-modifying complexes to p53 protein stability. Our findings may provide clues for therapeutic targeting of mutp53 in lymphoma and other cancers.
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000136739 7001_ $$00000-0001-6317-9296$$aSłabicki, Mikołaj$$b1
000136739 7001_ $$0P:(DE-He78)c9be4ab60d1090c3d315a2ca6905e9ea$$aHüllein, Jennifer$$b2$$udkfz
000136739 7001_ $$0P:(DE-He78)00086b00f36bb11578c336b3c94123a0$$aJentzsch, Marius$$b3$$udkfz
000136739 7001_ $$0P:(DE-He78)6867ed28952f2a9127613528c6a5cf8d$$aDalal, Vineet$$b4$$udkfz
000136739 7001_ $$aRabe, Sophie$$b5
000136739 7001_ $$0P:(DE-He78)dafca537433ee26708b96d89aba38d29$$aWagner, Lena$$b6$$udkfz
000136739 7001_ $$0P:(DE-He78)e8feda17d03b95bda3e8717e79dc07b8$$aWalther, Tatjana$$b7$$udkfz
000136739 7001_ $$00000-0001-7208-4117$$aKlapper, Wolfram$$b8
000136739 7001_ $$aProject, MMML Network$$b9$$eCollaboration Author
000136739 7001_ $$00000-0003-1038-1030$$aBohnenberger, Hanibal$$b10
000136739 7001_ $$00000-0002-8304-3385$$aRettel, Mandy$$b11
000136739 7001_ $$00000-0002-9211-0746$$aLu, Junyan$$b12
000136739 7001_ $$00000-0001-5011-0898$$aSmits, Arne H$$b13
000136739 7001_ $$00000-0001-9695-1692$$aStein, Frank$$b14
000136739 7001_ $$00000-0003-2011-9247$$aSavitski, Mikhail M$$b15
000136739 7001_ $$00000-0002-0474-2218$$aHuber, Wolfgang$$b16
000136739 7001_ $$aAylon, Yael$$b17
000136739 7001_ $$00000-0003-4311-7172$$aOren, Moshe$$b18
000136739 7001_ $$0P:(DE-He78)f3d5f16b49eb47520def635be98d5576$$aZenz, Thorsten$$b19$$eLast author$$udkfz
000136739 773__ $$0PERI:(DE-600)1468538-3$$a10.1182/blood-2017-09-806679$$gVol. 131, no. 25, p. 2789 - 2802$$n25$$p2789 - 2802$$tBlood$$v131$$x1528-0020$$y2018
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