title: SUMOylated ORC2 Recruits a Histone Demethylase to Regulate Centromeric Histone Modification and Genomic Stability.
abstract: Origin recognition complex 2 (ORC2), a subunit of the ORC, is essential for DNA replication initiation in eukaryotic cells. In addition to a role in DNA replication initiation at the G1/S phase, ORC2 has been shown to localize to the centromere during the G2/M phase. Here, we show that ORC2 is modified by small ubiquitin-like modifier 2 (SUMO2), but not SUMO1, at the G2/M phase of the cell cycle. SUMO2-modification of ORC2 is important for the recruitment of KDM5A in order to convert H3K4me3 to H3K4me2, a "permissive" histone marker for α-satellite transcription at the centromere. Persistent expression of SUMO-less ORC2 led to reduced α-satellite transcription and impaired pericentric heterochromatin silencing, which resulted in re-replication of heterochromatin DNA. DNA re-replication eventually activated the DNA damage response, causing the bypass of mitosis and the formation of polyploid cells. Thus, ORC2 sustains genomic stability by recruiting KDM5A to maintain centromere histone methylation in order to prevent DNA re-replication.
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA; Department of Cardiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA; The Central Lab at Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA; Department of Biochemistry and Molecular and Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jinke
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA; Center for Nuclear Receptors and Cell Signaling and Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Tasneem
authors.initials: T
authors.lastname: Bawa-Khalfe
authors.affiliation: Anhui Key Laboratory of Cellular Dynamics and Hefei National Laboratory for Physical Sciences at Nanoscale, University of Science and Technology of China, Hefei 230026, China.
authors.forename: Xuebiao
authors.initials: X
authors.lastname: Yao
authors.affiliation: The Central Lab at Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA; Department of Cardiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: etyeh@mdanderson.org.
authors.forename: Edward T H
authors.initials: ETH
authors.lastname: Yeh
mesh_terms: D045744:Cell Line, Tumor; D002503:Centromere / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D004260:DNA Repair; D016195:G2 Phase; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D051738:Origin Recognition Complex / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D056485:Retinoblastoma-Binding Protein 2 / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D058207:Sumoylation
chemical_list: D006657:Histones; C497224:ORC2 protein, human; D051738:Origin Recognition Complex; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2