Group IVA Cytosolic Phospholipase A 2 Regulates the G 2 -to-M Transition by Modulating the Activity of Tumor Suppressor SIRT2

Author:

Movahedi Naini Said1,Sheridan Alice M.1,Force Thomas2,Shah Jagesh V.134,Bonventre Joseph V.135

Affiliation:

1. Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

2. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA

3. Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

4. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA

5. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA

Abstract

ABSTRACT The G 2 -to-M transition (or prophase) checkpoint of the cell cycle is a critical regulator of mitotic entry. SIRT2, a tumor suppressor gene, contributes to the control of this checkpoint by blocking mitotic entry under cellular stress. However, the mechanism underlying both SIRT2 activation and regulation of the G 2 -to-M transition remains largely unknown. Here, we report the formation of a multiprotein complex at the G 2 -to-M transition in vitro and in vivo . Group IVA cytosolic phospholipase A 2 (cPLA 2 α) acts as a bridge in this complex to promote binding of SIRT2 to cyclin A-Cdk2. Cyclin A-Cdk2 then phosphorylates SIRT2 at Ser331. This phosphorylation reduces SIRT2 catalytic activity and its binding affinity to centrosomes and mitotic spindles, promoting G 2 -to-M transition. We show that the inhibitory effect of cPLA 2 α on SIRT2 activity impacts various cellular processes, including cellular levels of histone H4 acetylated at K16 (Ac-H4K16) and Ac-α-tubulin. This regulatory effect of cPLA 2 α on SIRT2 defines a novel function of cPLA 2 α independent of its phospholipase activity and may have implications for the impact of SIRT2-related effects on tumorigenesis and age-related diseases.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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