SUMO2/3 modification of cyclin E contributes to the control of replication origin firing

• Published in: Nature communications Vol. 4; no. 1; p. 1850
• Main Authors: Bonne-Andrea, Catherine, Kahli, Malik, Mechali, Francisca, Lemaitre, Jean-Marc, Bossis, Guillaume, Coux, Olivier
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.05.2013; Nature Publishing Group; Nature Pub. Group
• Subjects: 631/337/151/2355; 631/80/458/538; Animals; Biochemistry, Molecular Biology; Cell Extracts; Chromatin - metabolism; Cyclin E - metabolism; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-dependent kinases; DNA damage; DNA Replication; Enzymes; Genomes; Humanities and Social Sciences; Humans; Kinases; Life Sciences; multidisciplinary; Ovum - metabolism; Proteins; Replication Origin; S Phase; Science; Science (multidisciplinary); Small Ubiquitin-Related Modifier Proteins - metabolism; Sperm; Substrate Specificity; Sumoylation; Ubiquitin-Conjugating Enzymes - metabolism; Xenopus laevis - metabolism; Xenopus Proteins - metabolism; Yeast; France
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2875

The small ubiquitin-like modifier (SUMO) pathway is essential for the maintenance of genome stability. We investigated its possible involvement in the control of DNA replication during S phase by using the Xenopus cell-free system. Here we show that the SUMO pathway is critical to limit the number and, thus, the density of replication origins that are activated in early S phase. We identified cyclin E, which regulates cyclin-dependent kinase 2 (Cdk2) to trigger origin firing, as an S-phase substrate of this pathway. We show that cyclin E is dynamically and highly conjugated to SUMO2/3 on chromatin, independently of Cdk2 activity and origin activation. Moreover, cyclin E is the predominant SUMO2/3 target on chromatin in early S phase, as cyclin E depletion abolishes, while its readdition restores, the SUMO2/3 signal. Together, our data indicate that cyclin E SUMOylation is important for controlling origin firing once the cyclin E–Cdk2 complex is recruited onto replication origins. The organized initiation of DNA replication at sites throughout the genome must be carefully choreographed to maintain genome stability. Bonne-Andrea and colleagues show that protein SUMOylation controls the density of origin firing, and identify cyclin E as an important substrate in this context.