Although several studies have suggested that the functions of heterochromatin regulators may be regulated by post-translational modifications during cell cycle progression, regulation of the histone methyltransferase Suv39H1 is not fully understood. Here, we demonstrate a direct link between Suv39H1 phosphorylation and cell cycle progression. We show that CDK2 phosphorylates Suv39H1 at Ser391 and these phosphorylation levels oscillate during the cell cycle, peaking at S phase and maintained during S-G2-M phase. The CDK2-mediated phosphorylation of Suv39H1 at Ser391 results in preferential dissociation from chromatin. Furthermore, phosphorylation-mediated dissociation of Suv39H1 from chromatin causes an enhanced occupancy of JMJD2A histone demethylase on heterochromatin and alterations in inactive histone marks. Overexpression of phospho-mimic Suv39H1 induces early replication of heterochromatin, suggesting the importance of Suv39H1 phosphorylation in the replication of heterochromatin. Moreover, overexpression of phospho-defective Suv39H1 caused altered replication timing of heterochromatin and increases sensitivity to replication stress. Collectively, our data suggest that phosphorylation-mediated modulation of Suv39H1-chromatin association may be an initial step in heterochromatin replication.
Bibliographical noteFunding Information:
National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) [2011-0030049, in part]; National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea ; Basic Science Research Program through the NRF funded by the Ministry of Education, Science and Technology [2010-0010639]; NRF Grant funded by the Korean Government [2009-0075197]; Mid-career Researcher Program through NRF grant funded by the MEST [2009-0083772, in part]; Yonsei University Research Fund [2013-12-0087, in part, to S.H.P]; Brain Korea21Plus (BK21+) Program (S.H.P., S.E.Y. and Y.K.J.). Source of open access funding: NRF grant funded by the Korea government (MSIP) [2011-0030049]. Conflict of interest statement. None declared.
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