Human SLFN5 and its Xenopus Laevis ortholog regulate entry into mitosis and oocyte meiotic resumption

Gianmatteo Vit, Alexander Hirth, Nicolas Neugebauer, Bianca N. Kraft, Gianluca Sigismondo, Anna Cazzola, Claudia Tessmer, Joana Duro, Jeroen Krijgsveld, Ilse Hofmann, Michael Berger, Harald Klüter, Christof Niehrs, Jakob Nilsson*, Alwin Krämer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The Schlafen gene family was first described in mice as a regulator of thymocyte development. Further studies showed involvement of human orthologs in different processes related with viral replication, cellular proliferation, and differentiation. In recent years, a new role for human Slfn11 in DNA replication and chromatin remodeling was described. As commonly observed in many gene families, Slfn paralogs show a tissue-specific expression. This made it difficult to reach conclusions which can be valid in different biological models regarding the function of the different Schlafen proteins. In the present study, we investigate the involvement of SLFN5 in cell-cycle regulation and cell proliferation. A careful analysis of SLFN5 expression revealed that SLFN5 is highly expressed in proliferating tissues and that the protein is ubiquitously present in all the tissues and cell line models we analyzed. Very interestingly, SLFN5 expression oscillates during cell cycle, peaking during S phase. The fact that SLFN5 interacts with protein phosphatase 2A and that SLFN5 depletion causes cell cycle arrest and cellular apoptosis, suggests a direct involvement of this human paralog in cell cycle progression and cellular proliferation. We substantiated our in vitro and in cellulo results using Xenopus laevis oocytes to show that mRNA depletion of the unique Slfn gene present in Xenopus, whose protein sequence shares 80% of homology with SLFN5, recapitulates the phenotype observed in human cells preventing the resumption of meiosis during oocyte development.

Original languageAmerican English
Article number484
JournalCell Death Discovery
Volume8
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
We thank all members of the Krämer laboratory for advice and discussion. Priv.-Doz. Dr. Marion Schmidt-Zachmann for help with development of monoclonal antibodies. Samuel Loebell and Pavel Komaróv for help with experiments. Michael Kirsch, Ulrike Ackermann, Natalie Erbe-Hofmann, and Dimitria Garvanska for experimental support. Dr. Baubak Bajoghli from EMBL, Heidelberg, for many discussions and suggestions. We would like to thank the NNF CPR protein production and characterization facility for helping with producing purified SLFN5-DBD. We acknowlegde funding of DKFZ-MOST Israel Cooperation, the Deutsche Forschungsgemeinschaft (DFG KR 1981/4-1), and the Medical Faculty of Mannheim of the Heidelberg University. Work at the Novo Nordisk Foundation Center for Protein Research was supported by grant NNF14CC0001. This work was supported by a grant from Independent Research Fund Denmark (0134-00199B) to JN.

Funding Information:
We thank all members of the Krämer laboratory for advice and discussion. Priv.-Doz. Dr. Marion Schmidt-Zachmann for help with development of monoclonal antibodies. Samuel Loebell and Pavel Komaróv for help with experiments. Michael Kirsch, Ulrike Ackermann, Natalie Erbe-Hofmann, and Dimitria Garvanska for experimental support. Dr. Baubak Bajoghli from EMBL, Heidelberg, for many discussions and suggestions. We would like to thank the NNF CPR protein production and characterization facility for helping with producing purified SLFN5-DBD. We acknowlegde funding of DKFZ-MOST Israel Cooperation, the Deutsche Forschungsgemeinschaft (DFG KR 1981/4-1), and the Medical Faculty of Mannheim of the Heidelberg University. Work at the Novo Nordisk Foundation Center for Protein Research was supported by grant NNF14CC0001. This work was supported by a grant from Independent Research Fund Denmark (0134-00199B) to JN.

Publisher Copyright:
© 2022, The Author(s).

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