Rai R, et al. (2011) Small Ubiquitin-related Modifier Ligase Activity of Mms21 Is Required for Maintenance of Chromosome Integrity during the Unperturbed Mitotic Cell Division Cycle in Saccharomyces cerevisiae. J Biol Chem 286(16):14516-30
Abstract: The Sumo-ligase activity of Mms21/Nse2, a conserved member of the Smc5/6 complex, is required for resisting extrinsically induced genotoxic stress. We report that the Mms21 Sumo-ligase activity is also required during the unchallenged mitotic cell cycle in Saccharomyces cerevisiae. Sumo-ligase defective cells are slow growing and spontaneously incur DNA damage. These cells require caffeine sensitive Mec1-kinase dependent checkpoint signaling for survival even in the absence of extrinsically induced genotoxic stress. Sumo-ligase defective cells are sensitive to replication stress and display synthetic growth defects with DNA damage checkpoint defective mutants such as mec1, rad9 and rad24. MMS21 Sumo-ligase and Mediator of Replication Checkpoint gene (MRC1) are epistatic with respect to HU-induced replication stress or MMS-induced DNA damage sensitivity. Subjecting Mms21 Sumo-ligase deficient cells to transient replication stress results in enhancement of cell cycle progression defects such as mitotic delay and accumulation of hyperploid cells. Consistent with the spontaneous activation of the DNA damage checkpoint pathway observed in the Mms21 mediated sumoylation deficient cells, enhanced frequency of chromosome breakage and loss is detected in these mutant cells. A mutation in the conserved Cysteine-221 that is engaged in coordination of the zinc ion in loop 2 of the Mms21 SPL-RING E3-ligase catalytic domain results in strong replication stress sensitivity and also confers slow growth and Mec1 dependence to unchallenged mitotically dividing cells. Our findings establish Mms21 mediated sumoylation as a determinant of cell cycle progression and maintenance of chromosome integrity during the unperturbed mitotic cell division cycle in budding yeast.
|Status: Published||Type: Journal Article||PubMed ID: 21324902|
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