2. Academic Validation
  3. The Greatwall kinase safeguards the genome integrity by affecting the kinome activity in mitosis

The Greatwall kinase safeguards the genome integrity by affecting the kinome activity in mitosis

  • Oncogene. 2020 Oct;39(44):6816-6840. doi: 10.1038/s41388-020-01470-1.
Xavier Bisteau 1 2,  Joann Lee 3,  Vinayaka Srinivas 4,  Joanna H S Lee 3 5,  Joanna Niska-Blakie 3 6,  Gifford Tan 3,  Shannon Y X Yap 3,  Kevin W Hom 3,  Cheng Kit Wong 7,  Jeongjun Chae 8,  Loo Chien Wang 3 9,  Jinho Kim 10,  Giulia Rancati 7,  Radoslaw M Sobota 3 9,  Chris S H Tan 3 6 11,  Philipp Kaldis 12 13
Affiliations

Affiliations

  • 1 Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, 138673, Republic of Singapore. xbisteau@ulb.ac.be.
  • 2 IRIBHM-Université Libre de Bruxelles ULB, Campus Erasme Blg C, Brussels, Belgium. xbisteau@ulb.ac.be.
  • 3 Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, 138673, Republic of Singapore.
  • 4 Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, 169857, Republic of Singapore.
  • 5 Ewha Woman's University, 52 Ewhayeodae-gil, Daehyeon-dong, Seodaemun-gu, Seoul, Republic of Korea.
  • 6 Bioinformatics Institute (BII), A*STAR, Singapore, 138671, Republic of Singapore.
  • 7 Institute of Medical Biology, A*STAR, Singapore, 138648, Republic of Singapore.
  • 8 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Korea.
  • 9 Functional Proteomics Laboratory, IMCB, A*STAR, Singapore, 138673, Republic of Singapore.
  • 10 Samsung Genome Institute, Samsung Medical Center, Gangnam-gu, Seoul, 06351, Korea.
  • 11 Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, China.
  • 12 Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, 138673, Republic of Singapore. philipp.kaldis@med.lu.se.
  • 13 Department of Clinical Sciences, Clinical Research Centre (CRC), Lund University, Box 50332, 202 13, Malmö, Sweden. philipp.kaldis@med.lu.se.
PMID: 32978522 DOI: 10.1038/s41388-020-01470-1
Abstract

Progression through Mitosis is balanced by the timely regulation of phosphorylation and dephosphorylation events ensuring the correct segregation of chromosomes before cytokinesis. This balance is regulated by the opposing actions of CDK1 and PP2A, as well as the Greatwall kinase/MASTL. MASTL is commonly overexpressed in Cancer, which makes it a potential therapeutic Anticancer target. Loss of MASTL induces multiple chromosomal errors that lead to the accumulation of micronuclei and multilobulated cells in Mitosis. Our analyses revealed that loss of MASTL leads to chromosome breaks and abnormalities impairing correct segregation. Phospho-proteomic data for MASTL knockout cells revealed alterations in proteins implicated in multiple processes during Mitosis including double-strand DNA damage repair. In silico prediction of the kinases with affected activity unveiled NEK2 to be regulated in the absence of MASTL. We uncovered that, RAD51AP1, involved in regulation of homologous recombination, is phosphorylated by NEK2 and CDK1 but also efficiently dephosphorylated by PP2A/B55. Our results suggest that MastlKO disturbs the equilibrium of the mitotic phosphoproteome that leads to the disruption of DNA damage repair and triggers an accumulation of chromosome breaks even in noncancerous cells.

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