ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage.

Molecular Cell
Svetlana V KhoronenkovaGrigory L Dianov

Abstract

The deubiquitylation enzyme USP7/HAUSP plays a major role in regulating genome stability and cancer prevention by controlling the key proteins involved in the DNA damage response. Despite this important role in controlling other proteins, USP7 itself has not been recognized as a target for regulation. Here, we report that USP7 regulation plays a central role in DNA damage signal transmission. We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53. After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. Our findings provide a quantitative transmission mechanism of the DNA damage signal to coordinate a p53-dependent DNA damage response.

References

Mar 18, 2000·The Journal of Biological Chemistry·S FangA M Weissman
Apr 14, 2000·Oncogene·S de RozieresG Lozano
Jun 14, 2002·Trends in Cell Biology·Khalil AhmedClaude Cochet
Mar 13, 2003·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Flavio Meggio, Lorenzo A Pinna
Apr 1, 2004·Molecular Cell·Muyang LiWei Gu
May 1, 2004·Cell Cycle·Jordan M Cummins, Bert Vogelstein
Aug 18, 2004·Genes & Development·Paul R AndreassenToshiyasu Taniguchi
Dec 1, 2005·Molecular Cancer Research : MCR·Cécile-Marie Aliouat-DenisJorge E Vialard
Jul 18, 2006·Nature Cell Biology·Jun TangXiaolu Yang
Sep 12, 2006·Nature Cell Biology·Armando van der HorstBoudewijn M T Burgering
Dec 13, 2006·Cancer Cell·Ingo RingshausenGerard I Evan
Feb 24, 2007·Nature Reviews. Molecular Cell Biology·Greg B G MoorheadAnnegret Ulke-Lemée
Mar 24, 2007·Nature Reviews. Molecular Cell Biology·Karen H Vousden, David P Lane
Feb 13, 2008·Cancer Metastasis Reviews·Xiongbin LuLawrence A Donehower
May 5, 2009·Cell·Karen H Vousden, Carol Prives
May 20, 2009·Cell·Jan-Philipp Kruse, Wei Gu
Jul 21, 2009·Cell·Mathew E SowaJ Wade Harper
Sep 25, 2009·Nature Reviews. Cancer·Arnold J Levine, Moshe Oren
May 18, 2010·DNA Repair·Jason L ParsonsGrigory L Dianov

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Citations

Jun 14, 2013·Chromosoma·Petra SchwertmanJurgen A Marteijn
May 29, 2013·Cell Biochemistry and Biophysics·Xavier JacqStephen P Jackson
Mar 15, 2013·Nature Reviews. Molecular Cell Biology·Yosef Shiloh, Yael Ziv
Jan 1, 2013·Nucleic Acids Research·Svetlana V Khoronenkova, Grigory L Dianov
Nov 15, 2012·Genes & Cancer·Wenwei HuArnold J Levine
Jan 7, 2014·Acta Biochimica Et Biophysica Sinica·Yuhan ZhaoWenwei Hu
Sep 10, 2014·Nature Cell Biology·Ryotaro NishiStephen P Jackson
Mar 17, 2015·Proceedings of the National Academy of Sciences of the United States of America·Svetlana V Khoronenkova, Grigory L Dianov
Nov 29, 2014·The Journal of Investigative Dermatology·Shobhan GaddameedhiAziz Sancar
Feb 25, 2015·Scientific Reports·Chang PanJin-peng Sun
Jun 1, 2013·Developmental Dynamics : an Official Publication of the American Association of Anatomists·William H FosterYibin Wang
Aug 2, 2014·European Journal of Haematology·Alessandro MorottiGiuseppe Saglio
Apr 5, 2016·Oncogene·E MandatoF Piazza
Jul 17, 2015·IUBMB Life·Pranita HanpudeTushar Kanti Maiti
Jun 24, 2015·Genome Biology·Deborah A SandersShankar Balasubramanian
Apr 17, 2015·Molecular Biology of the Cell·Denis OstapenkoMark J Solomon
Nov 8, 2013·Cell Cycle·Bo LiuXingzhi Xu
Apr 14, 2015·Nature Communications·Hongmei CuiChunhong Yan
Dec 12, 2012·Cell Reports·Xiomaris M Cotto-RiosTony T Huang
Jun 8, 2013·Biochimica Et Biophysica Acta·Andreas K Hock, Karen H Vousden
Feb 20, 2015·Cell Death & Disease·J-J ParkK-H Baek
May 18, 2016·The Journal of Clinical Investigation·Qian WangLei Shi
Oct 30, 2016·Pathophysiology : the Official Journal of the International Society for Pathophysiology·Sergio Manzetti, Otto Andersen
Nov 10, 2017·Scientific Reports·Matthias BosshardBarbara van Loon
Dec 9, 2017·Molecular & Cellular Proteomics : MCP·Maria Rita SciutoTobias L Haas
May 22, 2018·Cell Biochemistry and Function·Farjana Yeasmin KhusbuHan-Chun Chen
Aug 8, 2018·International Journal of Molecular Sciences·Jaehyuk PyoJa-Eun Kim
Dec 9, 2015·Molecular and Cellular Biology·Younghoon Kee, Tony T Huang
Jul 30, 2014·Molecular and Cellular Biology·Neelam Chaudhary, Subbareddy Maddika
Sep 2, 2015·Molecular and Cellular Biology·Swapna Aravind GudipatyIván D'Orso
Jan 21, 2014·The Journal of Biological Chemistry·Julia DornUlrich Hübscher
Sep 13, 2018·EMBO Reports·Pablo Palazón-RiquelmeGloria López-Castejón
Sep 14, 2017·Biochemical Society Transactions·Sarah DarlingJudy M Coulson

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Methods Mentioned

BETA
immunoprecipitation
ionizing irradiation
FACS

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