Genetic interrogation of replicative senescence uncovers a dual role for USP28 in coordinating the p53 and GATA4 branches of the senescence program

Anna E. Mazzucco; Agata Smogorzewska; Chanhee Kang; Ji Luo; Michael R. Schlabach; Qikai Xu; Rupesh Patel; Stephen J. Elledge

doi:10.1101/gad.304857.117

Genetic interrogation of replicative senescence uncovers a dual role for USP28 in coordinating the p53 and GATA4 branches of the senescence program

¹Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
²Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
³The Rockefeller University, New York, New York 10065, USA;
⁴School of Biological Sciences, Seoul National University, Seoul 08826, South Korea;
⁵Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA;
⁶KSQ Pharmaceuticals, Cambridge, Massachusetts 02139, USA

Corresponding author: selledge{at}genetics.med.harvard.edu

Abstract

Senescence is a terminal differentiation program that halts the growth of damaged cells and must be circumvented for cancer to arise. Here we describe a panel of genetic screens to identify genes required for replicative senescence. We uncover a role in senescence for the potent tumor suppressor and ATM substrate USP28. USP28 controls activation of both the TP53 branch and the GATA4/NFkB branch that controls the senescence-associated secretory phenotype (SASP). These results suggest a role for ubiquitination in senescence and imply a common node downstream from ATM that links the TP53 and GATA4 branches of the senescence response.

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Supplemental material is available for this article.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.304857.117.

Received July 14, 2017.
Accepted September 19, 2017.

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