Issue No. 24, May 2019
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, MPh, PhD, FNAI, the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine and external affiliate members focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by VIMM members.      
VIMM scientists have discovered a novel regulatory mechanism governing mitotic function of Polo-like kinase 1 (PLK1).
 
  • PLK1 is a serine/threonine kinase that plays key roles in the control of the cell cycle.
  • PLK1 is under highly coordinated and multi-layered regulation. However, the regulatory pathways that control PLK1’s activity and function are not yet fully explored.
  • A recent study by Dr. Fu’s research group demonstrates SUMOylation is a novel important regulatory mechanism governing PLK1’s mitotic function.
  • Post-translational modifications (PTMs) of PLK1 cause its nuclear import and significantly increase protein stability, both of which allow for rapid change in the function of preexisting PLK1 during M phase, ensuring normal mitotic progression and genomic integrity.
  • This study has identified and characterized an important new regulatory mechanism governing PLK1’s function. Uncovering this regulatory pathway provides new insights into the biology of PLK1, which is essential for exploring PLK1’s potential as an target for cancer therapy.
 
 
SUMOylation promotes nuclear import and stabilization of PLK1 to support its mitotic function

As a pivotal mitotic regulator, PLK1 is under highly coordinated and multi-layered regulation. However, the pathways that control PLK1’s activity and function have just begun to be elucidated. PLK1 was recently shown to be functionally modulated by post-translational modifications, including phosphorylation and ubiquitination. This work reveals that a novel PTM, SUMOylation, also plays an essential role in regulating the mitotic function of PLK1. Ubc9 was recruited to PLK1, upon initial phosphorylation and activation by CDK1/cyclin B. By  in vivo  and  in vitro  SUMOylation assays, PLK1 was identified as a physiologically relevant SUMO-targeted protein, preferentially modified by SUMO-1. K492 in PLK1 is a major SUMO acceptor site. SUMOylation not only led to nuclear import of PLK1, but also significantly increased its protein stability by preventing the recruitment of APC/C cdh1 , the ubiquitin E3-ligase of PLK1. Resembling Ubc9 deficiency, cells expressing mutant PLK1-K492R protein exhibited mitotic aberrations characterized by prolonged mitotic progression, and misaligned and/or mis-segregated chromosomes, which could be rescued by reintroducing SUMOylation modification to PLK1. Collectively, these findings suggest that SUMOylation is another important regulatory mechanism governing PLK1 mitotic function to ensure normal mitotic progression and genomic integrity.
Figure legend: A. PLK1 is subject to SUMO modification, demonstrated by immunoprecipitation analysis. Representative time-lapse images are shown with the acquisition time relative to the onset of mitosis indicated on each image. SUMOylation of PLK1 contributes to normal cell cycle progression and genome stability. A lack of SUMO modification causes numerous mitotic defects. White arrows indicate misaligned chromosomes or lagging chromosomes. B. Model for SUMOylation-mediated regulation of PLK1’s function.
This research was supported by grants from the American Cancer Society (ACS Research Scholar Grant 127626-RSG-15-005-01-CCG to Z.F.), and the National Institutes of Health (NIH R01 CA191002 to Z.F.). The study was published in the Cell Reports November 21, 2017*.

Publication:

*Wen D, Wu J, Wang L, Fu Z. SUMOylation promotes nuclear import and stabilization of polo-like kinase 1 to support it mitotic function. Cell Reports . 2017 Nov 21; 21(8):2147-2159. PMCID: PMC5728694

About the Investigators: Zheng Fu, PhD is an Associate Professor of Human and Molecular Genetics (HMG), a member of the VCU Institute of Molecular Medicine (VIMM) and the VCU Massey Cancer Center (MCC), Virginia Commonwealth University, School of Medicine, Richmond, VA. Donghua Wen, PhD and Jianguo Wu, PhD, the co-first authors of this research study, are postdoctoral fellows in the Fu laboratory. Wei Wang, PhD is a visiting scholar in the Fu laboratory.