Cell-cycle regulation of non-enzymatic functions of the Drosophila methyltransferase PR-Set7

Amel Zouaz (1) , Céline Fernando (1) , Yannick Perez (1) , Claude Sardet (1) , Eric Julien (1) , Charlotte Grimaud (1)

1 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier

Tight cell-cycle regulation of the histone H4-K20 methyltransferase PR-Set7 is essential for the maintenance of genome integrity. In mammals, this mainly involves the interaction of PR-Set7 with the replication factor PCNA, which triggers the degradation of the enzyme by the CRL4CDT2 E3 ubiquitin ligase. PR-Set7 is also targeted by the SCFβ-TRCP ligase, but the role of this additional regulatory pathway remains unclear. Here, we show that Drosophila PR-Set7 undergoes a cell-cycle proteolytic regulation, independently of its interaction with PCNA. Instead, Slimb, the ortholog of β-TRCP, is specifically required for the degradation of the nuclear pool of PR-Set7 prior to S phase. Consequently, inactivation of Slimb leads to nuclear accumulation of PR-Set7, which triggers aberrant chromatin compaction and G1/S arrest. Strikingly, these phenotypes result from non-enzymatic PR-Set7 functions that prevent proper histone H4 acetylation independently of H4K20 methylation. Altogether, these results identify the Slimb-mediated PR-Set7 proteolysis as a new critical regulatory mechanism required for proper interphase chromatin organization at G1/S transition.

Domaines: Médecine humaine et pathologie; Cancer

Amel Zouaz, Céline Fernando, Yannick Perez, Claude Sardet, Eric Julien, et al.. Cell-cycle regulation of non-enzymatic functions of the Drosophila methyltransferase PR-Set7. Nucleic Acids Research, 2018, 46 (6), pp.2834-2849. ⟨10.1093/nar/gky034⟩. ⟨hal-02292938⟩