SUMOylated ORC2 Recruits a Histone Demethylase to Regulate Centromeric Histone Modification and Genomic Stability

• Published in: Cell reports (Cambridge) Vol. 15; no. 1; pp. 147 - 157
• Main Authors: Huang, Chao, Cheng, Jinke, Bawa-Khalfe, Tasneem, Yao, Xuebiao, Chin, Y. Eugene, Yeh, Edward T.H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.04.2016; Elsevier
• Subjects: Cell Line, Tumor; Centromere - metabolism; Chromatin Assembly and Disassembly; DNA Repair; G2 Phase; Genomic Instability; Histones - metabolism; Humans; Methylation; Origin Recognition Complex - genetics; Origin Recognition Complex - metabolism; Protein Processing, Post-Translational; Retinoblastoma-Binding Protein 2 - metabolism; Small Ubiquitin-Related Modifier Proteins - metabolism; Sumoylation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.02.091

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. [Display omitted] •ORC2 is SUMOylated from the late-S to G2/M phase of the cell cycle•ORC2 SUMOylation promotes recruitment of KDM5A to centromeres•Centromeric non-coding RNA transcription is deregulated in ORC2 SUMOylation mutant cells•ORC2 SUMOylation defect results in bypass of mitosis and polyploidy Huang et al. demonstrate that ORC2 SUMOylation is required for the recruitment of KDM5A to centromeres to maintain normal histone H3K4 methylation. Loss of ORC2 SUMOylation results in abnormal centromeric H3K4 methylation, leading to re-replication of heterochromatin DNA, abnormal mitosis, and formation of polyploidy.